Ribose linker and its conjugates

Abstract

In order to solve the problem of finding mechanisms and treatments for maintaining NAD+ levels, we provide a compound represented by formula 1.

Description

[Technical field]

[0001] The present disclosure provides a compound of formula 1: A-R1-A' (Formula 1) where A and A' are independently H or [ka] where A, A', and R1 are as described herein. Also provided are methods of making the compounds described herein, and uses of the compounds, for example, in NAD (nicotinamide adenine dinucleotide) increasing compositions. [Background technology]

[0002] In research into metabolic dysfunction and metabolic aging, the nicotinamide adenine dinucleotide (NAD) level increases with age and disease progression in patients. + These findings provide insight into the various roles played by NAD. + is known to decline as humans age, and NAD may be important for enhancing health benefits. + Finding mechanisms and treatments to maintain these levels is desirable.

[0003] Nicotinamide riboside and its derivatives (including nicotinate riboside, reduced form of nicotinamide riboside, nicotinamide mononucleotide, and nicotinate mononucleotide) are the building blocks of nicotinamide adenine dinucleotide (NAD + ) and its reduced form, NADH. NADH and NAD + Together, these are abbreviated as NAD. +Nicotinamide riboside, a precursor of nicotinamide riboside, has been shown to promote oxidative metabolism and protect against high-fat diet-induced obesity and inflammation in mice, resulting in great interest in nicotinamide riboside and its derivatives. The reduced form of nicotinamide riboside has also been shown to dramatically increase NAD levels in animal models. Because nicotinamide riboside is a naturally occurring compound, nicotinamide riboside and its derivatives have great potential as natural dietary supplements that may provide health benefits without causing side effects. Nicotinamide riboside and its derivatives are hydrophilic and require passive diffusional transporters to cross tissues and mammalian cell membranes. Nicotinamide riboside is also a substrate for the ubiquitous hydrolase purine phosphorylase and is readily metabolized by microbial phosphorylase, making it less available orally. The reduced form of nicotinamide riboside does not undergo these degradation processes and may therefore increase overall NAD enhancement when taken orally. This is true for the acid, nicotinic acid riboside, and phosphorylated species. However, an alternative approach to reduce hydrolytic degradation of nicotinamide riboside would be to prevent enzymatic degradation while facilitating uptake into cells for incorporation into the NAD biosynthetic pathway. Modification of the riboside moiety offers such an opportunity. However, such modifications must not only provide a means to bypass the degradative process to allow for enhanced NAD in cells, but also a means to manipulate the physicochemical properties of the highly polar species to provide a high payload, increase energy capacity, and make it available in cells despite transport limitations. Summary of the Invention

[0004] The present disclosure provides a compound represented by formula 1: A-R1-A' (Formula 1) where A and A' are independently H or [ka] where A, A', and R1 are as described herein.

[0005] The present disclosure further provides a compound represented by formula 2: [ka] where R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; Ac is an acetyl group.

[0006] The present disclosure further provides a compound represented by formula 3: [ka] where R3 is a substituted or unsubstituted C 1-4 Alkyl, C 2-4 C optionally substituted with alkenyl, or protected or free amine 1-3 or R3 is (i) a hydroxy group and (ii) an alkyl carboxylate. [ka] and Ac is an acetyl group.

[0007] The compounds provided herein can be conjugated, for example, to a nucleobase and / or nicotinamide or a salt, solvate, or derivative thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced form thereof.

[0008] Also provided are methods of making and using the compounds described herein, for example, in NAD increasing compositions. The following drawings form part of the present specification and are included to further demonstrate illustrative embodiments of certain aspects of the present invention. [Brief description of the drawings]

[0009] [Figure 1A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 4 in Synthesis Scheme 1 of Example 1. [Figure 1B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 4 in Synthesis Scheme 1 of Example 1. [Figure 1C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 4 in Synthesis Scheme 1 of Example 1. [Figure 2A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6a described in Example 2. [Figure 2B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6a described in Example 2. [Figure 2C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6a described in Example 2. [Figure 3A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6b described in Example 2. [Figure 3B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6b described in Example 2. [Figure 3C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6b described in Example 2. [Figure 4A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6c described in Example 2. [Figure 4B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6c described in Example 2. [Figure 4C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6c described in Example 2. [Figure 5A] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6d described in Example 2 are shown. [Figure 5B]Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6d described in Example 2 are shown. [Figure 5C] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6d described in Example 2 are shown. [Figure 6A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6e described in Example 2. [Figure 6B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6e described in Example 2. [Figure 6C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 6e described in Example 2. [Figure 7A] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6f described in Example 2 are shown. [Figure 7B] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6f described in Example 2 are shown. [Figure 7C] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6f described in Example 2 are shown. [Figure 8A] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6g described in Example 2 are shown. [Figure 8B] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6g described in Example 2 are shown. [Figure 8C] Illustrative 1H NMR, 13C NMR, and mass spectra of compound 6g described in Example 2 are shown. [Figure 9A] 1 shows exemplary 1H NMR and 13C NMR spectra of compound 6h described in Example 2. [Figure 9B] 1 shows exemplary 1H NMR and 13C NMR spectra of compound 6h described in Example 2. [Figure 10A] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8a described in Example 3. [Figure 10B] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8a described in Example 3. [Figure 10C] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra, respectively, of compound 8a described in Example 3. [Figure 11A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 8b described in Example 3. [Figure 11B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 8b described in Example 3. [Figure 11C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 8b described in Example 3. [Figure 12A] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8c described in Example 3. [Figure 12B] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8c described in Example 3. [Figure 12C] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8c described in Example 3. [Figure 13A] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8d described in Example 3 are shown. [Figure 13B] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8d described in Example 3 are shown. [Figure 13C] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8d described in Example 3 are shown. [Figure 14] 1 shows an exemplary 1H NMR spectrum of compound 8e described in Example 3. [Figure 15A] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8f described in Example 3. [Figure 15B] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8f described in Example 3. [Figure 15C] 1 shows exemplary 1H NMR, 13C NMR, and 19F NMR spectra of compound 8f described in Example 3. [Figure 16A] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8g described in Example 3 are shown. [Figure 16B] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8g described in Example 3 are shown. [Figure 16C] Illustrative 1H NMR, 13C NMR, and 19F NMR spectra of compound 8g described in Example 3 are shown. [Figure 17] 1 shows an exemplary 1H NMR spectrum of compound 8h described in Example 3. [Figure 18A] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 9b described in Example 4. [Figure 18B] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 9b described in Example 4. [Figure 18C] 1 shows exemplary 1H NMR, 13C NMR, and mass spectra of compound 9b described in Example 4. [Figure 19] 1 shows an exemplary 1H NMR spectrum of compound 6i described in Example 6. [Figure 20] 1 shows an exemplary 1H NMR spectrum of compound 8i described in Example 6. [Figure 21] 1 shows an exemplary 1H NMR spectrum of compound 17 described in Example 7. [Figure 22A] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22B] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22C]1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22D] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22E] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22F] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 22G] 1 shows exemplary 1H NMR spectra of compounds 6(a-g) described in Example 1. [Figure 23A] 1 shows an exemplary 1H NMR spectrum of compound 8g before column chromatography as described in Example 2. [Figure 23B] 1 shows exemplary 1H NMR and 13C NMR spectra of compound 8g after column chromatography as described in Example 2. [Figure 23C] 1 shows exemplary 1H NMR and 13C NMR spectra of compound 8g after column chromatography as described in Example 2. [Figure 24A] Figures 24A-33 relate to Example 5. Exemplary 1H NMR and 19F NMR spectra of NRTA triflate prior to ion exchange are shown. [Figure 24B] Figures 24A-33 relate to Example 5. Exemplary 1H NMR and 19F NMR spectra of NRTA triflate prior to ion exchange are shown. [Figure 25A] Exemplary 1H NMR and 19F NMR spectra of NRTA chloride after (top), before (middle), and during (bottom) ion exchange. [Figure 25B] Exemplary 1H NMR and 19F NMR spectra of NRTA chloride after (top), before (middle), and during (bottom) ion exchange. [Figure 26A]1 shows exemplary 1H NMR and 19F NMR spectra of compound 10g (NRLR-Cl) after column purification and ion exchange. [Figure 26B] 1 shows exemplary 1H NMR and 19F NMR spectra of compound 10g (NRLR-Cl) after column purification and ion exchange. [Figure 27] 1 shows exemplary 19F NMR spectra of NRLR in D2O before ion exchange chromatography (bottom) and NRLR-Cl in D2O after ion exchange chromatography (top). [Figure 28] Exemplary 1H NMR spectra of NRLR-Cl after column and ion exchange (top), NRLR after column purification (middle), and NRLR before column purification (bottom) are shown. [Figure 29] 1 shows an exemplary 1H NMR spectrum of NRLR without column chromatography ("crude NRLR"). [Diagram 30] Illustrative 1H NMR spectra of crude NRLR before (top) and after (bottom) ion exchange. [Figure 31A] 1 shows an exemplary 19F NMR spectrum and mass spectrum of crude NRLR after ion exchange. [Figure 31B] 1 shows an exemplary 19F NMR spectrum and mass spectrum of crude NRLR after ion exchange. [Diagram 32] Illustrative 19F NMR spectra of crude NRLR before (top) and after (bottom) ion exchange. [Figure 33A] Exemplary 1H NMR, 19F NMR, 13C NMR, and HSQC spectra of compound 10g after reverse phase column chromatography are shown. [Figure 33B] Exemplary 1H NMR, 19F NMR, 13C NMR, and HSQC spectra of compound 10g after reverse phase column chromatography are shown. [Figure 33C] Exemplary 1H NMR, 19F NMR, 13C NMR, and HSQC spectra of compound 10g after reverse phase column chromatography are shown. [Figure 33D] Exemplary 1H NMR, 19F NMR, 13C NMR, and HSQC spectra of compound 10g after reverse phase column chromatography are shown. [Figure 34A] Figures 34A-39 relate to Example 9. Exemplary 1H NMR spectra of purine nucleoside phosphorylase (PNP) enzyme activity assay using nitrate reductase (NR). [Figure 34B] 1 shows exemplary 1H NMR spectra of purine nucleoside phosphorylase (PNP) enzyme activity assay using NR and NRTA. The top panel shows NR 5 minutes after PNP addition. The second, third, and fourth panels show 20 minutes after PNP addition, 0 minutes after PNP addition, and NRTA without PNP, respectively. [Figure 34C] Exemplary 1H NMR spectra of a PNP assay using NRTA are shown at the indicated time points over a longer time course: 5 min, 20 min, 24 h after PNP addition, or before PNP addition. [Diagram 35] 1 shows an exemplary 1H NMR spectrum of NRLR triflate in 100% dimethyl sulfoxide (DMSO). [Diagram 36] Exemplary 1H NMR spectra of lipase assays with NRLR at the indicated times: 5 min, 30 min, 1 h, 6 h, and 12 h after addition of lipase. [Figure 37] Exemplary 1H NMR spectra of lipase assays with NRLR and high concentration lipase at the indicated times: 5 min, 6 h, and 12 h after lipase addition. [Figure 38] Exemplary 1H NMR spectra of the PNP assay for NRLR are shown at the indicated times: 5 min, 1 h, 6 h, 12 h, 18 h, 24 h after PNP addition, or before PNP addition. [Figure 39]Exemplary 1H NMR spectra of a PNP assay for NR adipate at the indicated times: 5 min, 15 min, 30 min, 1 h, 6 h, 12 h, 18 h after PNP addition, or before PNP addition. [Figure 40A] 1 shows exemplary 1H NMR spectra of PNP assays for NR adipate, NR malonate, NR laurate, and NR chloride after incubation with PNP for 1 day. [Figure 40B] 1 shows exemplary 1H NMR spectra of PNP assays for NR adipate, NR malonate, NR laurate, and NR chloride after incubation with PNP for 2 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure provides novel ribose linker compounds that can be potentially functionalized with a biologically active agent of interest or a prodrug thereof, as shown in Formula 1: A-R1-A' (Formula 1) where A and A' are independently H, or [ka] and where A, A', and R1 are as described herein.

[0011] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0012] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or one or more than one element.

[0013] The term "or" in the claims is used to mean "and / or" unless expressly stated to refer to alternatives only or the alternatives are mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only and "and / or."

[0014] As used herein, the terms "comprising" (and any variation or form of "comprising", such as "comprise" or "comprises"), "having" (and any variation or form of "having", such as "have" or "has"), "including" (and any variation or form of "including", such as "includes" or "include"), or "containing" (and any variation or form of "containing", such as "contains" or "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0015] Use of the term "for example" and its abbreviation "eg" means that the particular term recited is representative of examples and embodiments of the disclosure that are not intended to be limited to the particular example referenced or cited, unless otherwise specified.

[0016] As used herein, "about" means plus or minus 10% of the value provided. When ranges are provided, they are inclusive of the boundaries. "About" can additionally or alternatively mean within 10% of the stated value, within 5% of the stated value, or in some cases within 2.5% of the stated value; or, "about" can mean a value rounded to the nearest significant figure.

[0017] As used herein, "between" refers to a range that includes the endpoints of the range, for example, numbers between x and y expressly include the numbers x and y and all numbers that fall within the range between x and y.

[0018] The term "Ac" refers to acetyl.

[0019] The term "alkyl" refers to a linear or branched acyclic alkyl moiety, preferably containing one or more carbon atoms, e.g., from about 2 to about 50 carbon atoms, or from about 4 to about 40 carbon atoms, or from about 6 to about 30 carbon atoms, or from about 8 to about 24 carbon atoms. The alkyl moiety can be optionally substituted with a group as described herein, e.g., halo, hydroxyl, amino (e.g., primary, secondary, or tertiary amino), carboxyl, carboxyalkyl, methoxy, ethoxy, alkoxyamino, alkoxyamido, trifluoromethyl, sulfonyl, sulfonamido, acetamido, cyano, nitro, or any combination thereof.

[0020] The term "alkenyl" refers to a linear or branched unsaturated acyclic hydrocarbon moiety containing at least one double bond, e.g., 1, 2, 3, 4, 5, or more than 5 double bonds, and preferably containing from about 2 to about 50 carbon atoms, or from about 4 to about 40 carbon atoms, or from about 6 to about 30 carbon atoms, or from about 8 to about 24 carbon atoms. The alkenyl moiety can be optionally substituted with a group as described herein, e.g., halo, hydroxyl, amino, amido, carboxyl, carboxyalkyl, methoxy, ethoxy, alkoxyamino, alkoxyamido, trifluoromethyl, sulfonyl, sulfonamido, acetamido, cyano, nitro, azido, or any combination thereof. Examples of suitable alkenyl moieties include octen-1-yl, nonen-1-yl, decen-1-yl, stearyl, oleyl, linoleyl, linolenyl, arachidonyl, eicasopentaenyl, and docosahexaenyl.

[0021] The term "alkynyl" refers to a linear or branched unsaturated acyclic hydrocarbon moiety containing at least one triple bond, e.g., 1, 2, 3, 4, 5, or more than 5 triple bonds, and preferably containing from about 2 to about 50 carbon atoms, or from about 4 to about 40 carbon atoms, or from about 6 to about 30 carbon atoms, or from about 8 to about 24 carbon atoms. The alkynyl moiety can be optionally substituted with a group described herein, e.g., halo, hydroxyl, amino (e.g., primary, secondary, or tertiary amino), carboxyl, carboxyalkyl, methoxy, ethoxy, alkoxyamino, alkoxyamido, trifluoromethyl, sulfonyl, sulfonamido, acetamido, cyano, nitro, or any combination thereof.

[0022] The term "alkoxy" includes straight-chain or branched oxy-containing moieties, each having an alkyl moiety as described above, for example, from about 2 to about 50 carbon atoms, or from about 4 to about 40 carbon atoms, or from about 6 to about 30 carbon atoms, or from about 8 to about 24 carbon atoms. The term "alkoxyalkyl" includes alkyl moieties having one or more alkoxy moieties attached to the alkyl moiety.

[0023] The term "aryl" refers to a fully unsaturated monocyclic or polycyclic carbocyclic ring. Examples of such moieties include substituted or unsubstituted phenyl (or benzyl), naphthyl, and anthracenyl. The term "aryl", when used alone or within other terms, refers to a monocyclic or polycyclic aromatic ring structure containing 1 to 4 rings, which may be attached together in a pendant manner or fused. Such aryl groups may bear one or more substituents, such as, but not limited to, alkyl, hydroxy, halo, haloalkyl, amino, nitro, cyano, alkoxy, and alkylamino. The term "aryl" refers to both ring structures consisting of only carbon (carboaryl) and ring structures containing carbon and heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen (heteroaryl). The term "aryl" also includes polycyclic heteroaryls, such as, for example, indole, phthalide (benzofuran), 1H-indazole, 1H-pyrrolo[2,3-b]pyridine, indoline, tetrahydroquinoline, 2,3-dihydrobenzofuran, and the like.

[0024] The term "BOC" or "Boc" refers to tert-butoxycarbonyl.

[0025] The term "prodrug" refers to a chemical derivative of an active parent drug that releases the active parent drug upon spontaneous or enzymatic biotransformation. The term "prodrug" includes variations or derivatives of the compounds of the invention that have groups cleavable under metabolic conditions, including solvolysis or enzymatic degradation. In some embodiments, prodrugs are pharmacologically inactive or exhibit reduced activity relative to their active parent drug.

[0026] The term "substituted" means that any one or more hydrogen atoms are replaced with any suitable substituent, provided that the normal valence is not exceeded and that the substitution results in a stable compound. Suitable substituents include, but are not limited to, alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl (including alkylcarbonyl and arylcarbonyl), phosphate, amino (including alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino and alkylarylamino), thiol (including alkylthiol, arylthiol and thiocarboxylate), sulfate, nitro, cyano and azide.

[0027] Ribose monomer The present disclosure provides novel ribose linker compounds that can be functionalized with a biologically active agent of interest or a prodrug thereof, as shown in Formula 1: A-R1-A' (Formula 1) where A and A' are independently H, or [ka] and where A and A' are not both H, and: If one of A or A' is H, R1 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, or alkenylaryl; or If A and A' are not both H, then R1 is a substituted or unsubstituted C 1-4 Alkyl, C 2-4 C optionally substituted with alkenyl, polyethylene glycol (PEG) ester alkyl, or protected or free amine 1-3 is an alkyl carboxylate; Ac is an acetyl group.

[0028] In some embodiments, one of A or A' in formula 1 is hydrogen. Thus, in some embodiments, the compound of formula 1 is [ka] is: For example, a compound of formula 2. [ka]

[0029] Preferably, R1 in formula 1 or R2 in formula 2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 It is alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl.

[0030] Preferably, R1 in formula 1 or R2 in formula 2 is an unsubstituted C 2-40 Alkyl or unsubstituted C 4-36 Alkyl or unsubstituted C 6-30 Alkyl or unsubstituted C 8-24 For example, R1 or R2 and the oxycarbonyl (OC=O) to which it is attached together form a saturated fatty acid ester group, such as caprylic acid ("capryloyl"; C 8 ), capric acid ("caproyl"; C 10 ), lauric acid ("lauroyl"; C 12 ), myristic acid ("myristoyl"; C 14 ), palmitic acid ("palmitoyl"; C 16 ), stearic acid ("stearoyl"; C 18 ), arachidic acid ("arachidoyl"; C 20 ), behenic acid ("behenoyl"; C 22 ), or tetracosanoic acid ("tetracosanoyl"; C 24 In certain embodiments, R1 or R2 can form an ester such as C 12 It is an alkyl.

[0031] In some embodiments, the compound of Formula 1 or Formula 2 is: [ka] It is.

[0032] In a further embodiment, R of formula 1 or R of formula 2 is an unsubstituted C 2-40 Alkenyl or unsubstituted C 4-36 Alkenyl or unsubstituted C 6-30 Alkenyl or unsubstituted C 8-24 It is alkenyl. For example, R1 or R2 and the oxycarbonyl (OC=O) to which it is attached can combine to form an unsaturated fatty acid ester group, such as an ester of myristoleic acid ("myristoleoyl"), palmitoleic acid ("palmitoleoyl"), sapienic acid ("sapienoyl"), oleic acid ("oleoyl"), elaidic acid ("elaidyl"), vaccenic acid ("vaccenoyl"), linoleic acid ("linolenoyl"), linoelaidic acid ("linoelaioyl"), α-linolenic acid ("α-linolenoyl"), γ-linolenic acid ("γ-linolenoyl"), arachidonic acid ("arachidonoyl"), eicosapentaenoic acid ("eicosapentaenoyl"), erucic acid ("ercoyl"), or docosahexaenoic acid ("docosahexaenoyl"), etc. In some embodiments, R1 or R2 and the oxycarbonyl to which it is attached form an ester of an essential fatty acid, such as oleic acid, linoleic acid, or alpha-linolenic acid. In further embodiments, R1 or R2 and the oxycarbonyl to which it is attached form an ester of an omega-3 fatty acid, such as alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid.

[0033] In yet another embodiment, R1 of formula 1 or R2 of formula 2 is any of the C 2-40 Alkyl, C 4-36 Alkyl, C 6-30 Alkyl, or C 8-24 substituted alkyl, such as alkyl, or C as described herein; 2-40 Alkenyl, C4-36 Alkenyl, C 6-30 Alkenyl, or C 8-24 Alkenyl is substituted alkenyl such as alkenyl.Suitable alkyl and alkenyl substituents are known to those skilled in the art.As a non-limiting example, alkyl or alkenyl can be substituted at any one or more positions along the alkyl or alkenyl chain with one or more of alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl, alkylcarbonyl, arylcarbonyl, phospho, amino, alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino and alkylarylamino, thiol, alkylthiol, arylthiol, thiocarboxylate, sulfate, nitro, cyano, azide, or any combination thereof.

[0034] In yet another embodiment, R1 of formula 1 or R2 of formula 2 is aryl, alkylaryl, or alkenylaryl. For example, R1 or R2 can be substituted or unsubstituted phenyl or benzyl. Suitably, the substitution can be at any position of the aryl. Suitably, the substitution includes alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl, alkylcarbonyl, arylcarbonyl, phospho, amino, alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino and alkylarylamino, thiol, alkylthiol, arylthiol, thiocarboxylate, sulfate, nitro, cyano, and azide. In certain embodiments, R1 or R2 is substituted benzyl, such as amino-substituted benzyl. In certain embodiments, R1 or R2 is para-aminobenzyl. In further embodiments, R1 or R2 is alkylaryl or alkenylaryl, such as C 1-24 Alkyl or C 1-24 alkenyl, and aryl groups as described herein, such as phthalide.

[0035] In yet another embodiment, R1 of formula 1 or R2 of formula 2 comprises a pharma- ceutical active agent. Suitably, R1 or R2 comprises a vitamin, such as retinol. Suitably, R1 or R2 and the oxycarbonyl to which it is attached form a succinate ester of retinol. In a further embodiment, R1 or R2 and the oxycarbonyl to which it is attached form a mycophenolate ester. Thus, in an embodiment, the compound of formula 1 or formula 2 is: [ka] It is.

[0036] In further embodiments, R1 of formula 1 or R2 of formula 2 is an alkyl polyethylene glycol (PEG) ester, i.e., R1 or R3 is -O(CH 2 )-mO(CH 2 CH 2 O)nCH 3 where m is an integer from 1 to 10 and n is an integer from 5 to 200. In embodiments, the alkyl PEG ester contains from about 5 to about 200 ethylene glycol units, or from about 8 to about 150 ethylene glycol units, or from about 10 to about 100 ethylene glycol units, or from about 20 to about 80 ethylene glycol units, or from about 30 to about 70 ethylene glycol units, or from about 40 to about 60 ethylene glycol units. In some embodiments, the compound of Formula 1 or Formula 2 is: [ka] It is.

[0037] Ribose dimer In certain embodiments, neither A nor A' of formula 1 is hydrogen. In such embodiments, the compound of formula 1 is: [ka] and For example, a compound of formula 3: [ka] It is.

[0038] In an embodiment, the compound of formula 3 is: [ka] or It is a mixture of them.

[0039] Preferably, R1 of formula 1 or R3 of formula 3 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, polyethylene glycol (PEG) ester alkyl, or protected or free amine 1-3 It is an alkyl carboxylate.

[0040] Preferably, R1 of formula 1 or R3 of formula 3 is an unsubstituted C 1-10 Alkyl or unsubstituted C 1-8 Alkyl or unsubstituted C 1-6 Alkyl or unsubstituted C 1-4 For example, R1 or R3 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 --It could be.

[0041] In some embodiments, R1 or R3 and the oxycarbonyl group to which it is attached are malonic acid diesters (R1 or R3 is -CH 2 -); succinic acid diester (R1 or R3 is -CH 2 CH 2 -); glutaric acid diester (R1 or R3 is -CH 2 CH 2 CH 2 -); or adipic acid diesters (R1 or R3 is -CH2 CH 2 CH 2 CH 2 -) together.

[0042] For example, a compound of formula 1 or formula 3 may be: [ka] It can be one of the following.

[0043] In further embodiments, R of formula 1 or R of formula 3 is, for example, C as described herein. 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, or C 1-4 and substituted alkyl such as alkyl. As a non-limiting example, the alkyl may be substituted at any one or more positions along the alkyl chain with one or more of alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl, alkylcarbonyl, arylcarbonyl, phospho, amino, alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino and alkylarylamino, thiol, alkylthiol, arylthiol, thiocarboxylate, sulfate, nitro, cyano, azide, or any combination thereof. Suitably, R1 or R3 is an alkyl substituted with an amino group. The amino group may include a protected or unprotected amine (also referred to herein as a "free" amine). In certain embodiments, R1 or R3 is an alkyl substituted with a Boc-protected amine (e.g., C 1-3 In further embodiments, R1 or R3 is an alkyl (e.g., C 1-3 In yet another embodiment, R1 or R3 is [ka] substituted alkyl (e.g., C 1-3alkyl).

[0044] In certain embodiments, the compound of Formula 1 or Formula 3 is: [ka] It is.

[0045] Preferably, R1 of formula 1 or R3 of formula 3 is an unsubstituted C 2-10 Alkenyl or unsubstituted C 2-8 Alkenyl or unsubstituted C 2-6 Alkenyl or unsubstituted C 2-4 alkenyl, where the alkenyl contains one or more double bonds. For example, R1 or R3 can be -CH=CH-, -CH=CHCH 2 -, -CH 2 CH=CH-, -CH=CHCH 2 CH 2 -, -CH 2 CH=CHCH 2 -, or -CH 2 CH 2 In a further example, R1 or R3 may include multiple double bonds that may be located at any position within the alkenyl chain. For example, R1 or R3 may be -CH=C=CH-, -CH=C=CHCH 2 -, -CH 2 It can be -CH=C=CH-, or -CH=C=C=CH-. Suitably, R1 or R3 and the oxycarbonyl group to which it is attached together form a fumarate or maleate ester. In one embodiment, the compound of formula 1 or formula 3 is: [ka] It is.

[0046] In further embodiments, R of formula 1 or R of formula 3 is, for example, any of the C 2-10 Alkenyl, C 2-8 Alkenyl, C 2-6 Alkenyl, or C 2-4and substituted alkenyls such as alkenyl. As non-limiting examples, alkenyls can be substituted at any one or more positions along the alkenyl chain with one or more of alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl, alkylcarbonyl, arylcarbonyl, phospho, amino, alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino and alkylarylamino, thiol, alkylthiol, arylthiol, thiocarboxylate, sulfate, nitro, cyano, azide, or any combination thereof.

[0047] In yet another embodiment, R1 of formula 1 or R3 of formula 3 is an alkyl PEG ester, i.e., R1 or R3 is -O(CH 2 )mO(CH 2 CH 2 O)n-, where m is an integer from 1 to 10 and n is an integer from 5 to 200. In embodiments, the alkyl PEG ester contains from about 5 to about 200 ethylene glycol units, or from about 8 to about 150 ethylene glycol units, or from about 10 to about 100 ethylene glycol units, or from about 20 to about 80 ethylene glycol units, or from about 30 to about 70 ethylene glycol units, or from about 40 to about 60 ethylene glycol units. In some embodiments, the compound of Formula 1 or Formula 3 is: [ka] It is.

[0048] Ribose trimer (trimer) In a further embodiment, R3 of the compound of formula 3 is (i) a hydroxyl group and (ii) [ka] It contains a carbon bonded to one of the following:

[0049] Suitably, the compound of formula 3 is: [ka] It is.

[0050] In an embodiment, the compound of formula 3 [ka] Either where R3 is (i) a hydroxyl group and (ii) [ka] is a carbon bonded to

[0051] In an embodiment, the compound of formula 3 [ka] Either where R3 is (i) a hydroxyl group and (ii) [ka] is a carbon bonded to

[0052] Nucleoside Complexes In some embodiments, the ribose linker compound provided herein, for example, the compound of formula 1, formula 2, or formula 3, is coupled to one or more additional compounds.The one or more additional compounds can be biologically active agents, for example, therapeutic agents.Preferably, the biologically active agent is a nucleobase.As used herein, "nucleobase" includes all naturally occurring nucleobases typically found in DNA and RNA, such as adenine, cytosine, guanine, thymine, and uracil; modified nucleobases, such as hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, and 5-hydroxymethylcytosine; artificial nucleobases, also called nucleobase analogs, such as isoguanine and isocytosine; and pyridine nucleobases, such as nicotinamide and / or its salts, solvates, or derivatives thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, and their reduced forms.

[0053] Suitably, one or more further compounds, e.g., a nucleobase, are attached to the ribose of formula 1 at the 1' carbon position of the ribose ring, e.g., to provide a compound of formula 4, where the one or more further compounds are represented as R4: B-R1-B' (Formula 4) where B and B' are independently H, or [ka] and where Ac is an acetyl group; B and B' are not both H; and R1 is as described herein for formula 1. In some embodiments, when one of B or B' in formula 4 is H, R1 can be a substituted or unsubstituted C 8-24 Alkyl, C 8-24 In a further embodiment, when B and B' are not both H, R1 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4C optionally substituted with alkenyl, PEG ester alkyl, or protected or free amine 1-3 It is an alkyl carboxylate.

[0054] Suitably, one or more further compounds, e.g., a nucleobase, are attached to the ribose of formula 2 at the 1' carbon position of the ribose ring, e.g., to provide a compound of formula 6, where the one or more further compounds are represented as R4: [ka] where Ac is an acetyl group and R2 is as described herein for formula 2. In some embodiments, R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 It is alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl.

[0055] Suitably, one or more further compounds, e.g., a nucleobase, are attached to the ribose of formula 3 at the 1' carbon position of the ribose ring, e.g., to provide a compound of formula 8, where the one or more further compounds are represented as R4 and R4': [ka] where Ac is an acetyl group and R3 is as described herein for formula 3. In some embodiments, R3 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, or protected or free amine 1-3 It is an alkyl.

[0056] In a further embodiment, R3 is (i) a hydroxyl group and (ii) [ka] It contains a carbon bonded to one of the following:

[0057] In some embodiments, the compound of formula 8 is [ka] It is.

[0058] Suitably, R4 of formula 4, formula 6, and formula 8, R4' of formula 8, and / or R4'' of formula 8 are nucleobases. Nucleobases are described herein. In an embodiment, R4, R4', and R4'' are each independently a nucleobase selected from adenine, cytosine, guanine, thymine, and uracil; a modified nucleobase selected from hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, and 5-hydroxymethylcytosine; an artificial nucleobase selected from isoguanine and isocytosine; and a pyridine-containing compound selected from nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, and reduced forms thereof. In certain embodiments, R4, R4', and / or R4'' are nicotinamide or a salt, solvate, or derivative thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof. The structures of nicotinamide and related compounds are shown below: [ka] [ka]

[0059] The attachment points of R4, R4', and / or R4'' to the ribose of formula 4, formula 6, and / or formula 8 can be determined by one of skill in the art. Suitably, in embodiments, the nucleobase is attached via a nitrogen atom, such as the nitrogen at position 1 of a pyrimidine ring (e.g., cytosine, uracil, thymine, etc.) or the nitrogen at position 9 of a purine ring (e.g., adenine, guanine, etc.). In embodiments, the nicotinamide and / or related compounds described herein are attached via a nitrogen in a pyridine or dihydropyridine ring. Those of skill in the art will understand that when oxidized nicotinamide and its derivatives are attached via a nitrogen atom in the ring, the nitrogen atom carries a +1 charge. Those of skill in the art will further understand that when reduced nicotinamide and its derivatives are attached via a nitrogen atom in the ring, the nitrogen atom in the ring is no longer bound to hydrogen.

[0060] Suitably, nicotinamide, or a salt, solvate, or derivative thereof, is attached to a compound of formula 4, 6, or 8 via the nitrogen of the pyridine ring to provide a nicotinamide ribose (NR) complex, or a salt, solvate, or derivative thereof.

[0061] Nicotinamide ribose complex Nicotinamide riboside (NR) is the precursor of nicotinamide adenine dinucleotide (NAD or NAD+), nicotinamide adenine dinucleotide phosphate (NADP or NADP+), and their respective phosphorylated forms (NADH and NADPH, respectively), all of which are important enzyme cofactors. For example, NAD+ is involved in metabolic processes such as energy production, DNA repair, cellular detoxification, inflammatory responses, and protein folding. The structure of NR is shown below: [ka]

[0062] As indicated above, NR is a quaternary salt and can form an ionic bond with a counterion, such as a counteranion. Examples of counter ions include the anions of suitable organic acids, such as formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, and triflic acid (i.e., trifluoromethanesulfonic acid), theophylline acetate, and 8-halotheophylline, e.g., 8-bromotheophylline, and the like. Further examples of pharma- ceutically acceptable inorganic or organic acid counterions include the pharma- ceutically acceptable salts described in J. Pharm. Sci. 66(1):2 (1977).

[0063] Suitably, R4 of formula 4 is nicotinamide or a derivative thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof, thereby providing a compound of formula 5, where R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof: C-R1-C' (Formula 5) where C and C' are independently H, or [ka] and where Ac is an acetyl group; C and C' are not both H; and R1 is as described herein for formula 1. In some embodiments, when one of C or C' in formula 4 is H, R1 is a substituted or unsubstituted C as described herein. 8-24 Alkyl, C 8-24In a further embodiment, when C and C' are not both H, R1 is a substituted or unsubstituted C as described herein. 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, PEG ester alkyl, or protected or free amine 1-3 It is an alkyl carboxylate.

[0064] Suitably, R4 of formula 6 is nicotinamide or a derivative thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof, thereby providing a compound of formula 7, where R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof: [ka] where Ac is an acetyl group and R2 is as described herein for formula 2. In some embodiments, R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 It is alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl.

[0065] Suitably, R1 of formula 5 or R2 of formula 7 is an unsubstituted C 8-24 In an exemplary embodiment, the compound of Formula 5 or Formula 7 is [ka] It is.

[0066] One of skill in the art will appreciate that while the NR derivative structures described herein include a triflate counter anion, the triflate may be replaced with any suitable counter anion, e.g., as described herein.

[0067] Suitably, R1 of formula 5 or R2 of formula 7 comprises a pharma- ceutical active agent as described herein, e.g., R1 or R2 and the oxycarbonyl to which it is attached form a mycophenolate ester. In an exemplary embodiment, the compound of formula 5 or formula 7 is: [ka] It is.

[0068] Suitably, R1 of formula 5 or R2 of formula 7 is an alkyl PEG ester as described herein, for example, comprising from about 5 to about 200 ethylene glycol units, preferably from about 8 to about 150 ethylene glycol units, preferably from about 10 to about 100 ethylene glycol units, preferably from about 20 to about 80 ethylene glycol units, preferably from about 30 to about 70 ethylene glycol units, or preferably from about 40 to about 60 ethylene glycol units. In an exemplary embodiment, the compound of formula 5 or formula 7 is: [ka] It is.

[0069] In further embodiments, R4 of formula 8 is nicotinamide or a derivative thereof, such as dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof, thereby providing a compound of formula 9, wherein R5 and R5' are each independently nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or a reduced form thereof: [ka] where Ac is an acetyl group and R3 is as described herein for formula 3. In some embodiments, R3 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, or protected or free amine 1-3 It is an alkyl.

[0070] In a further embodiment, R3 is (i) a hydroxyl group and (ii) [ka] containing a carbon bonded to one of wherein R5, R5', and R5'' are each independently nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof.

[0071] In some embodiments, the compound of formula 9 is [ka] and wherein R5, R5', and R5'' are each independently nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof.

[0072] Suitably, R1 of formula 5 or R3 of formula 9 is an unsubstituted C 1-4 In an embodiment, the compound of formula 5 or formula 9 is: [ka] Either one of the following.

[0073] Suitably, R1 of formula 5 or R3 of formula 9 is a C 2-4 alkenyl. In an embodiment, the compound of formula 5 or formula 9 is: [ka] It is.

[0074] Suitably, R1 of formula 5 or R3 of formula 9 is a C substituted or unsubstituted amine, optionally substituted with a protected or free amine, as described herein. 1-3 In an embodiment, the compound of formula 5 or formula 9 is: [ka] It is.

[0075] Suitably, R1 of formula 5 or R3 of formula 9 is an alkyl PEG ester as described herein, e.g., comprising from about 5 to about 200 ethylene glycol units, preferably from about 8 to about 150 ethylene glycol units, preferably from about 10 to about 100 ethylene glycol units, preferably from about 20 to about 80 ethylene glycol units, preferably from about 30 to about 70 ethylene glycol units, or preferably from about 40 to about 60 ethylene glycol units, or about 10 ethylene glycol units, or about 20 ethylene glycol units, or about 30 ethylene glycol units, or about 40 ethylene glycol units, or about 50 ethylene glycol units, or about 60 ethylene glycol units, or about 70 ethylene glycol units, or about 80 ethylene glycol units, or about 90 ethylene glycol units, or about 100 ethylene glycol units. In an exemplary embodiment, the compound of formula 5 or formula 9 is: [ka] It is.

[0076] In some embodiments, compounds of the disclosure, e.g., nucleoside and / or nicotinamide ribose conjugates provided herein, are substantially resistant to enzymatic hydrolysis, such as by lipases, phosphorylases (purine nucleoside phosphorylase (PNP), and the like). As used herein, "substantially resistant to enzymatic hydrolysis" means that the compound is not hydrolyzed for at least 15 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours, at least 18 hours, or at least 24 hours after contact with a hydrolytic enzyme, e.g., lipase or phosphorylase.

[0077] Manufacturing method In embodiments, the disclosure provides methods of making the compounds described herein.

[0078] Suitably, the method of making a compound of any one of formulas 1-3 or a salt, solvate, or derivative thereof comprises: (a) adding a protecting group to the 5'-carbon of D-ribose to form a 5'-protected ribose; (b) acetylating the hydroxy groups at the 1', 2', and 3' carbons of the 5'-protected ribose to form an acetylated, 5'-protected ribose; (c) deprotecting the 5'-carbon of the acetylated, 5'-protected ribose to form an acetylated, 5'-deprotected ribose; and (d) coupling the acetylated, 5'-deprotected ribose with a reactant comprising R1, R2, and / or R3 to form a compound of any one of formulas 1-3. In an embodiment, the method further comprises: (e) reacting a compound of any one of formulas 1-3 with a functionalized nucleobase, such as a functionalized nicotinamide, to form a compound of any one of formulas 4-9.

[0079] Protecting groups and corresponding deprotection procedures are known to those of skill in the art. Suitable protecting groups for alcohols (such as the alcohol group at the 5' carbon of ribose) and methods for their removal include, but are not limited to, the following: Acetyl (Ac) - can be removed with acid or base Benzoyl (Bz) - can be removed with acid or base Benzyl (Bn) – can be removed by hydrogenolysis β-Methoxyethoxymethylether (MEM) - can be removed with acid Dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT) - can be removed with weak acid Methoxymethyl ether (MOM) - can be removed with acid Methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT) - can be removed by acid and hydrogenolysis p-Methoxybenzyl ether (PMB) - can be removed by acid, hydrogenolysis, or oxidation (e.g. DDQ) p-Methoxyphenyl ether (PMP) - can be removed by oxidation Methylthiomethyl ether - can be removed with acid Pivaloyl (Piv) - can be removed by acids, bases, or reducing agents Tetrahydropyranyl (THP) - can be removed with acid Tetrahydrofuran (THF) - can be removed with acid Trityl (triphenylmethyl, Tr) - can be removed by acid and hydrogenolysis Silyl ethers such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS or TBS), triisopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers - can be removed by acids or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride, HF-Py, or HF-NEt3) Methyl ether - cleavage with TMSI in dichloromethane, acetonitrile, or chloroform, or BBr in dichloromethane 3 Can be removed by cleavage with Ethoxyethyl ether (EE) - can be removed by cleavage

[0080] In some embodiments, the protecting group is a trityl group. Preferably, step (a) of the method comprises contacting D-ribose with trityl chloride to add a trityl group to the 5'-carbon of the ribose ring. Furthermore, step (c) of the method preferably comprises removing the trityl protecting group using an acid, such as acetic acid.

[0081] Methods of acetylation are known to those of skill in the art. An exemplary acetylating agent used in step (b) of the present process is acetic anhydride ("Ac 2 Further suitable acetylating agents include, but are not limited to, acetyl chloride, ketene, thioacetic acid, and the like.

[0082] Suitably, after the deprotection step, the acetylated, 5'-deprotected ribose comprises a hydroxy group at the 5'-carbon ("5'-hydroxy group"). In an embodiment, the coupling step of the method comprises contacting the acetylated, 5'-deprotected ribose of step (c) with a reactant that (i) comprises R1, R2, and / or R3 as described herein; and (ii) is capable of reacting with the 5'-hydroxy group. In some embodiments, the reactant is a monocarboxylic acid for R1, R2, and / or R3. In further embodiments, the reactant is a dicarboxylic acid for R1, R2, and / or R3. In yet another embodiment, the reactant is an acid anhydride for R1, R2, and / or R3. In yet another embodiment, the reactant is an acid chloride for R1, R2, and / or R3.

[0083] In embodiments where the reactant is a monocarboxylic acid or acid chloride at R1, the reactant is coupled with an acetylated, 5'-deprotected ribose to form a compound of formula 1 where one of A or A' is H. In embodiments where the reactant is a dicarboxylic acid or acid anhydride at R1, the reactant is coupled with an acetylated, 5'-deprotected ribose to form a compound of formula 1 where A or A' is not both H.

[0084] In a further embodiment, the reactant is a monocarboxylic acid or acid chloride at R2 which is coupled with an acetylated, 5'-deprotected ribose to form a compound of formula 2. In a further embodiment, the reactant is a dicarboxylic acid or acid anhydride at R3 which is coupled with an acetylated, 5'-deprotected ribose to form a compound of formula 3.

[0085] Suitably, the coupling is carried out in the presence of a coupling agent. For example, coupling reagents that convert hydroxy and carboxylic acids or acid anhydrides to esters are known to those skilled in the art. In an embodiment, the coupling agent is a carbodiimide reagent. Non-limiting examples of carbodiimide reagents include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), and 1-cyclohexyl-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMCT or CMC). The coupling reaction may also include a catalyst, such as, for example, 4-dimethylaminopyridine (DMAP). In certain embodiments, the acetylated, 5'-deprotected ribose is coupled with reactants that include R1, R2, and / or R3 in the presence of DCC or EDC and DMAP.

[0086] In embodiments, the methods herein include batch and semi-continuous processes that allow for the production of a compound of any one of formulas 1-9, a salt, solvate, or derivative thereof, where the use of solvents is minimized and conversion and reaction times are optimized through the use of closed conditions, continuous liquid-liquid extraction, and / or mechanochemistry, and optimized purification procedures.

[0087] As used herein, the term "solvent" includes water, water with an ionic compound dissolved therein, acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, t-butyl alcohol ("TBA"), 2-butanone, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane ("DCE"), diethylene glycol, diethyl ether ("Et 20"), diglyme (diethylene glycol dimethyl ether), 1,2-dimethoxyethane ("DME"), N,N-dimethylformamide ("DMF"), dimethyl sulfoxide ("DMSO"), 1,4-dioxane, ethanol, ethyl acetate ("EtOAc"), ethylene glycol, glycerin, heptane, hexamethylphosphoramide ("HMPA"), hexamethylphosphortriamide ("HMPT"), hexane, methanol ("MeOH"), methyl t-butyl ether ("MTBE"), methylene chloride ("DCM", "CH 2 Cl 2 "), N-methyl-2-pyrrolidinone ("NMP"), nitromethane, pentane, petroleum ether, 1-propanol ("n-propanol", "n-PrOH"), 2-propanol ("isopropanol", "iPrOH"), pyridine, tetrahydrofuran ("THF"), toluene, triethylamine ("TEA", "Et 3 "N"), o-xylene, m-xylene, and / or p-xylene, etc. Solvent types can include hydrocarbon, aromatic, aprotic, polar, alcoholic, and mixtures thereof.

[0088] As used herein, "mechano-chemical mixing," "mechanochemistry," and "mechamical processing" refer to techniques known to those skilled in the art in which chemical starting materials and / or reagents having different solubility characteristics are reacted, generally without solvent, for example, by direct milling, liquid assisted milling, triturating, mixing, or grinding. Interchangeable terms can include "mechanic-chemical," and the like. See, e.g., Ravalico et al., "Rapid synthesis of nucleotide pyrophosphate linkages in a ball mill" Org Biol Chem 9:6496 (2011);Hasa et al., "Cocrystal Formation through Mechanochemistry: From Neat and Liquid-Assisted Grinding to Polymer-Assisted Grinding" Angewandte Chemie 127:7371 (2015);Crossey et al., "Atom efficient synthesis of pyrimidine and purine nucleosides by ball milling" RSC Adv 5:58116 (2015);and Johnston et al., "Applications of Mechanochemistry for the Synthesis of DNA on Ionic Liquid Supports" Chemistry - Methods 1:1-8 (2021). Mechanochemistry is further described, e.g., in U.S. Patent No. 9,975,915. The disclosures of each of these references are incorporated herein by reference in their entirety for all purposes, and particularly with respect to the methods of "mechanochemical mixing," "mechanochemistry," and "mechanical processing."

[0089] The term "liquid-assisted mixing" as used herein refers to a technique known to those skilled in the art in which the rate of solid-state grinding is accelerated by the addition of small amounts of liquid during mixing. It has been found that not only does the addition of small amounts of liquid accelerate solid-state reactions, but in many cases the addition of small amounts of liquid also allows the formation of new solid-state morphologies that cannot be produced by other methods. See, e.g., Shan et al., "Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics," Chem Comm 2002:2732-2373 (2002). Furthermore, it has been found that the exact outcome of solid-state grinding can be controlled by careful selection of the added liquid. See, e.g., Trask et al., "Achieving Polymorphic and Stoichiometric Diversity in Cocrystal Formation: Importance of Solid-State Grinding, Powder X-ray Structure Differentiation, and Seeding," Crystal Growth & Design 5:2233 (2005). Furthermore, this liquid-assisted mixing approach has been demonstrated to be much more effective in exploring alternative solid forms of drug candidates than other previously used methods such as traditional solution crystallization or melt growth. See, e.g., Karki et al., "Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding," Molecular Pharmaceutics 4:347 (2007); and Trask et al., "Screening for crystalline salts via mechanochemistry," Chem Comm 2006:51 (2006).Liquid assisted mixing is a fast and environmentally friendly method as it does not require the use of large amounts of solvents, reducing waste and improving cost efficiency.

[0090] In embodiments, the coupling reaction is carried out, for example, by mechanochemical reaction in a ball mill jar. The ball milling conditions can be selected by one of skill in the art, and can be, for example, milling for about 10 minutes to about 60 minutes, or about 15 minutes to about 40 minutes, or about 20 minutes to about 30 minutes, or about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, or more than 60 minutes, at a frequency of about 10 Hz to about 60 Hz, or about 20 Hz to about 50 Hz, or about 30 Hz to about 40 Hz, or about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 Hz. In some embodiments, the ball milling is carried out at about 30 Hz for about 20 to about 40 minutes or about 20 to about 30 minutes.

[0091] Those skilled in the art will appreciate that in addition to mechanochemistry techniques, conventional solution chemistry can be used in the preparation of compounds of any one of Formulas 1-9 described herein.

[0092] In some embodiments, a compound of any one of formulas 1-3 is contacted with a functionalized nucleobase to form a corresponding compound of any one of formulas 4-6. In further embodiments, a compound of any one of formulas 1-3 is contacted with a functionalized nicotinamide to form a corresponding compound of any one of formulas 7-9.

[0093] The functionalized nucleobase or functionalized nicotinamide comprises a functional group capable of reacting with an ester, for example an ester at the 1' ribose carbon position of any one of formulas 1-3. Preferably, the functional group is attached to the amide nitrogen of the nicotinamide. Preferably, the functionalized nucleobase or functionalized nicotinamide comprises a trialkylsilyl group, for example a trimethylsilyl group. In an exemplary embodiment, the functionalized nicotinamide is N-trimethylsilyl-nicotinamide, also known as nicotinamide TMS: [ka]

[0094] Suitably, a functional nucleobase or functional nicotinamide, for example comprising a trialkylsilyl group, is coupled with a compound of formula 1-3 in the presence of a catalyst. In embodiments, the catalyst comprises a Lewis acid, such as trimethylsilyl trifluoromethanesulfonate ("TMSOTf"). In some embodiments, the coupling is carried out by mechanochemical reaction, for example in a ball mill jar with a minimal amount of solvent (e.g., anhydrous dichloromethane). Mechanochemistry and ball milling are described herein. In some embodiments, a compound of any one of formulas 1-3 is mixed with a functionalized nucleobase or functionalized nicotinamide and ball milled for about 10 minutes to about 60 minutes, or about 15 minutes to about 40 minutes, or about 20 minutes to about 30 minutes, or about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, or more than 60 minutes at a frequency of about 10 Hz to about 60 Hz, or about 20 Hz to about 50 Hz, or about 30 Hz to about 40 Hz, or about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 Hz. In some embodiments, the ball milling is performed at about 30 Hz for about 20 to about 40 minutes or about 20 to about 30 minutes. The resulting product may be a compound of any one of formulas 4-9. In embodiments where a compound of any one of formulas 1-3 is mixed with nicotinamide TMS, the resulting product is a compound corresponding to any one of formulas 7-9, where R5 is nicotinamide and the compound includes a triflate counter anion.

[0095] In some embodiments, the nicotinamide of any one of formulas 7-9 is, for example, sodium dithionite (Na 2 S 2 O 4), thereby providing compounds of formulas 7-9, in which R5 is dihydronicotinamide. A further example of a suitable reducing agent is sodium borohydride (NaBH 4 ).

[0096] In further embodiments, nicotinamide having a triflate counter anion of any one of formulas 7-9 is ion-exchanged with a different counter anion, such as, for example, chloride. Further non-limiting examples of counter anions are described herein. Ion exchange can be carried out using any suitable ion exchange resin, such as bromide resins, which can be functionalized to include the desired counter anion to be exchanged, and AmberLite® resins available from DuPont.

[0097] R3 is an unsubstituted C 1-4 Exemplary methods for preparing compounds of formula 3, which are alkyl (hereafter referred to as compounds 6a-h), are as follows: [ka]

[0098] Suitably, compounds 6a-h are used to prepare cycloalkyl groups in which R is an unsubstituted C 1-4 The alkyl compounds of formula 9 (hereafter referred to as compounds 10a-h) are prepared as follows: [ka]

[0099] An exemplary method for preparing a compound of formula 2, where R2 is an alkyl PEG ester described herein (hereinafter designated as compound 6i), is as follows: [ka]

[0100] Suitably, compound 6i is used to prepare a compound of formula 7, where R2 is an alkyl PEG ester as described herein (hereinafter referred to as compound 8i), as follows: [ka]

[0101] An exemplary method for preparing a compound of formula 3, where R3 is an alkyl PEG ester described herein (hereinafter designated as compound 17), is as follows: [ka]

[0102] Suitably, compound 17 is used to prepare a compound of formula 9, where R3 is an alkyl PEG ester as described herein (hereinafter referred to as compound 18), as follows: [ka]

[0103] Compositions and Methods of Use In an embodiment, a compound provided herein may be included in the composition, for example, a compound of any one of formulas 1-9, preferably a compound of any one of formulas 4-9, more preferably a compound of any one of formulas 7-9. In an exemplary embodiment, provided herein is an NAD increasing composition that may be administered to a subject in need thereof. Suitably, the NAD increasing composition includes a compound of formula 7, formula 8, formula 9, or a combination thereof.

[0104] In an exemplary embodiment, the composition is an oral formulation, including liquids, drops, sprays, solutions, gels, powders, suspensions, or solid formulations such as lozenges, capsules, tablets, pills, gel capsules, buccal or sublingual formulations.

[0105] In embodiments, the composition comprises one or more compounds of any one of Formulas 7-9 in an amount of about 100 mg to about 1000 mg, or about 200 mg to about 800 mg, or about 300 mg to about 700 mg, or about 400 to about 600 mg, or about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In embodiments, the composition comprises about 100 mg to about 1000 mg, or about 200 mg to about 800 mg, or about 300 mg to about 700 mg, or about 400 to about 600 mg, or about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of nicotinamide riboside (NR). For example, one molar equivalent of the compound of formula 9 provides 2 or 3 molar equivalents of NR, and thus a formulation intended to provide 500 mg of NR may suitably contain 167 mg or 250 mg of the compound of formula 9.

[0106] In embodiments, the composition further comprises one or more of i) a sirtuin-activating compound, ii) a CD38 inhibitory compound, and iii) a poly ADP-ribose polymerase (PARP) inhibitory compound.

[0107] As used herein, a "sirtuin-activating compound" or STAC is an NAD +Sirtuins are compounds that activate sirtuins, a group of enzymes that use acetylcholine to remove acetyl groups from proteins. Examples of sirtuin-activating compounds include polyphenols such as resveratrol, butein, piceatannol, isoliquiritigenin, fisetin, and quercetin. The amount of the sirtuin-activating compound is preferably contained in the compositions described herein in an amount of about 25 mg to about 1000 mg, about 100 mg to about 1000 mg, about 25 mg to about 500 mg, about 25 mg to about 200 mg, about 25 mg to about 250 mg, about 30 mg to about 225 mg, about 40 mg to about 200 mg, about 45 mg to about 250 mg, or about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg.

[0108] As used herein, a "CD38 inhibitor compound" refers to a compound that inhibits NAD + The term "CD38 inhibitor" refers to a compound that inhibits the phospholipase CD38. Examples of CD38 inhibitor compounds include flavonoids such as quercetin and apigenin. The amount of the CD38 inhibitor compound is preferably about 25 mg to about 1000 mg, about 100 mg to about 1000 mg, about 25 mg to about 500 mg, about 25 mg to about 200 mg, about 25 mg to about 250 mg, about 30 mg to about 225 mg, about 40 mg to about 200 mg, about 45 mg to about 250 mg, or about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg in the composition described herein.

[0109] As used herein, "poly ADP ribose polymerase (PARP) inhibitor compounds" refers to compounds that inhibit poly ADP ribose polymerase, a protein family involved in many cellular processes such as DNA repair, genomic stability, and programmed cell death. PARP family proteins include PARP1, PARP2, VPARP (PARP4), tankyrase-1 and -2 (PARP-5a or TNKS, and PARP-5b or TNKS2). Others include PARP3, PARP6, TIPARP (or "PARP7"), PARP8, PARP9, PARP10, PARP11, PARP12, PARP14, PARP15, and PARP16. Examples of PARP inhibitor compounds include olaparib, rucaparib, and niraparib. The amount of the PARP inhibitor compound is preferably contained in the composition described herein in an amount of about 25 mg to about 1000 mg, about 100 mg to about 1000 mg, about 25 mg to about 500 mg, about 25 mg to about 200 mg, about 25 mg to about 250 mg, about 30 mg to about 225 mg, about 40 mg to about 200 mg, about 45 mg to about 250 mg, or about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg.

[0110] Preferably, the composition also contains pterostilbene, which is a polyphenolic derivative of resveratrol and is an NAD + Like its precursor, it promotes metabolic health. The chemical structure of pterostilbene is shown below: [ka]

[0111] In some embodiments, derivatives, salts, solvates, or prodrugs of pterostilbene can be used in the compositions described herein. In certain embodiments, pterostilbene can be substituted and / or combined with epsilon-viniferin and / or resveratrol.

[0112] As described herein, the compositions used in the treatment are suitably formulated for oral administration, i.e., in oral formulations. Oral solid formulations are reviewed in Chapter 89 of Remington's Pharmaceutical Sciences, 18th Edition, 1990 (Mack Publishing Co. Easton Pa. 18042). Solid formulation forms include tablets, capsules, pills, lozenges or lozenges, cachets, pellets, powders, or granules, or the materials are incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, or liposomes. Such compositions may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the disclosed substances. See, for example, pages 1435-1712 of Remington's Pharmaceutical Sciences, 18th Edition, 1990 (Mack Publishing Co., Easton, Pa. 18042). The compositions may be prepared in liquid form or in dry powder (e.g., lyophilized) form. Liposomal or proteinoid encapsulation may be used to formulate the composition. Liposomal encapsulation may be used, and liposomes may be derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556). See also Marshall, K. In: Modem Pharmaceutics Edited by GS Banker and CT Rhodes, Chapter 10, 1979. The formulation may include a peptide (or a chemically modified form thereof) and an inactive ingredient that protects the compound in the stomach environment and releases the biologically active substance in the intestine.

[0113] For example, the compounds of formula 7, formula 8, and / or formula 9, pterostilbene, nicotinamide mononucleotide, niacin, epsilon-viniferin, and / or resveratrol, or derivatives thereof described herein, can be chemically modified to make oral administration of the compound effective. A possible chemical modification is to bind at least one moiety of the component molecule itself, which allows for uptake into the bloodstream from the stomach or intestine, or directly into the intestinal mucosa. Also possible is an increase in the overall stability of one or more chemical components and an increase in circulation time in the body. Certain embodiments may be pharmaceutical compositions. Certain embodiments may be dietary supplements.

[0114] Certain embodiments provide liquid dosage forms for oral administration, including pharma- ceutically acceptable emulsions, solutions, suspensions, and syrups, which may contain other ingredients, including inert diluents, adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening and flavoring agents.

[0115] It may be possible to provide a controlled release oral formulation. Controlled release may include, but is not limited to, delayed release and pH-dependent release. In certain embodiments, the compound of formula 7, formula 8, and / or formula 9, or a derivative thereof, may be incorporated into microcapsules, microparticles, nanoparticles, etc., to affect the release of the active ingredient through the use of coatings. In certain embodiments, the compound of formula 7, formula 8, and / or formula 9, or a derivative thereof, may be incorporated into an inert matrix, such as a resin, that allows for release by either diffusion or leaching mechanisms. Slowly degenerating inert matrices may also be incorporated into the formulation.

[0116] A modified release oral formulation may be provided. Modified release may allow for a specific release profile. An extended release oral formulation may be provided. Extended release may allow for the active ingredient to be released over a desired period of time. Further discussion of various release formulations and associated terminology can be found in Extended-Release Dosage Forms by Lesczek Krowczynski (1987, CRC Press, Inc.).

[0117] In one aspect, the controlled, modified or extended release oral formulation is in the form of a tablet, capsule, or microbead for oral administration. In other aspects, the controlled, modified or extended release formulation containing the appropriate and effective therapeutic amount of the desired ingredient may be a pill, powder, granule, sterile parenteral solution or suspension, oral solution or suspension, oil-water emulsion, as well as implants and microencapsulated release systems.

[0118] Other formulations may provide controlled, modified, or extended release profiles. The compositions of the present invention may include conventional pharmaceutical binders, excipients, and additives, which, when used in sufficient amounts, may serve to control, modify, or sustain release. Coating agents, such as plasticizers, may be used to enhance the controlled, modified, or extended release properties of the compositions of the present invention.

[0119] For oral formulations, the location of release may be the stomach, small intestine (duodenum, jejunum, ileum), or large intestine. Release may avoid the deleterious effects of the stomach environment by protecting the drug (or derivative) or releasing the drug (or derivative) beyond the stomach environment, e.g., into the intestine. To ensure complete gastric resistance, a coating that is temporarily impermeable to at least pH 5.0 is useful. Examples of the more common inactive ingredients used as enteric coatings include cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), poly(methacrylic acid-co-ethyl acrylate) 1:1, cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, and natural shellac resin. These coatings may also be used as mixed films.

[0120] In an exemplary embodiment, the composition may be provided in a soft capsule. The soft capsule may be prepared using techniques known to those skilled in the art. For example, soft capsules are typically manufactured using a rotary die encapsulation process. The active agent formulation is fed into the encapsulation machine by gravity. In an embodiment, the formulation includes pharmaceutical excipients such as olive oil, gelatin, glycerin, purified water, beeswax, sunflower lecithin, silicon dioxide, titanium dioxide, colorants, microcrystalline cellulose, hypromellose, vegetable magnesium stearate, and / or silica.

[0121] The capsule shell can include one or more plasticizers, such as glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyalcohols having 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof, hi one embodiment, the plasticizer is glycerin.

[0122] In addition to plasticizers, the capsule shell may include other suitable shell additives, such as opacifiers, colorants, humectants, preservatives, flavorings, buffer salts and acids.

[0123] When the encapsulated active agent is sensitive to light, opacifiers are used to make the capsule shell opaque.Suitable opacifiers include, but are not limited to, titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.In some embodiments, the opacifier is titanium dioxide.

[0124] Colorants may be used for marketing and product identification and / or differentiation purposes. Suitable colorants include synthetic and natural dyes, and combinations thereof.

[0125] Humectants can be used to reduce the water activity of the softgel capsule. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions. Dry, properly stored softgel capsules have a low water activity, so the greatest microbial risk comes from molds and yeasts. Preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid, such as methyl, ethyl, propyl, butyl, and heptyl (collectively known as "parabens"), or combinations thereof.

[0126] In embodiments, the compounds described herein are administered to a subject in need thereof, for example, via a composition described herein. In embodiments, the compounds of Formula 7, Formula 8, Formula 9, or combinations thereof are administered to a subject in an amount of about 50 mg to about 1500 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 125 mg to about 900 mg, about 150 mg to about 850 mg, about 200 mg to about 700 mg, about 200 mg to about 500 mg, about 1000 mg to about 1500 mg, or about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. Suitably, these amounts are administered to a subject daily in the form of a single composition or multiple compositions. Those skilled in the art will understand how to adjust the amount of compound based on the amount of nicotinamide to be administered. For example, in an embodiment where one molar equivalent of the compound contains two molar equivalents of NR (e.g., a compound of formula 9), the amount of compound administered is reduced by half. In an embodiment, pterostilbene or a derivative thereof is further administered to the subject in an amount of, for example, about 25 mg to about 1000 mg, about 100 mg to about 1000 mg, about 25 mg to about 500 mg, about 25 mg to about 200 mg, about 25 mg to about 250 mg, about 30 mg to about 225 mg, about 40 mg to about 200 mg, about 45 mg to about 250 mg, or about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg. Preferably, these amounts are administered to the patient daily in a single composition or in multiple compositions.

[0127] In additional exemplary embodiments, the compounds and / or compositions described herein are provided as oral formulations, topical formulations, injection or infusion formulations, inhalable or nebulizable formulations. In embodiments, the various components of the composition (e.g., compounds of formula 7, formula 8, and / or formula 9; pterostilbene; and / or additional components described herein) are provided in the same composition. In embodiments, the components of the composition are provided in separate compositions and are administered together at the same time or at different times.

[0128] Suitably, the method of treatment or prevention described herein comprises administering to a subject in need thereof a composition comprising a combination of about 200 mg to about 700 mg of a compound described herein, e.g., a compound of Formula 7, Formula 8, and / or Formula 9, and about 25 mg to about 200 mg of pterostilbene. In an embodiment, the composition comprises about 500 mg of a compound described herein, e.g., a compound of Formula 7, Formula 8, and / or Formula 9, and about 100 mg of pterostilbene. In an embodiment, the composition comprises about 250 mg of a compound described herein, e.g., a compound of Formula 7, Formula 8, and / or Formula 9, and about 50 mg of pterostilbene. In an embodiment, the composition is administered daily, twice a day, every other day, every third day, or once a week. Administration can be via any route of administration described herein.

[0129] These methods can include the use of the compositions described herein, in which the active agent (i.e., a compound of Formula 7, Formula 8, and / or Formula 9) is administered as a liquid in a dissolved (e.g., in a solution) or dispersed (e.g., in a suspension) state in the composition. The solution or suspension can be prepared using one or more pharma- ceutically acceptable excipients. Pharmaceutically acceptable excipients are described herein and include, but are not limited to, surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, pH adjusters, flavorings, and combinations thereof.

[0130] In embodiments, the compositions described herein are administered in a dosing regimen over a period of days, weeks, or months. Dosing may be multiple doses per day or once per day. When dosing is administered over multiple days, weeks, or months, each dose may not be equal. Dosages in a dosing regimen may vary according to the amounts and ranges disclosed herein. Preferably, the compositions described herein are administered daily for a period of at least 4 weeks, preferably at least 1 month, or at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. The compositions described herein may also be administered to a patient for a period of one year or more, including the patient's lifetime.

[0131] All references cited herein, including patents, patent applications, articles, textbooks, and the like, and the references cited therein, are hereby incorporated by reference in their entirety, unless already cited otherwise. Exemplary embodiments Embodiment 1. A compound of formula 1: A-R1-A' (Formula 1) In formula 1, A and A' are independently H or [ka] and where A and A' are not both H, and: When one of A or A' is H, R1 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, or alkenylaryl; or If A and A' are not both H, then R1 is a substituted or unsubstituted C 1-4 Alkyl, C 2-4 C optionally substituted with alkenyl, alkyl polyethylene glycol (PEG) esters, or protected or free amines 1-3 is an alkyl carboxylate; and Ac is an acetyl group. Embodiment 2. The compound of embodiment 1, wherein R1 is an alkyl PEG ester. Embodiment 3. The compound of embodiment 2, wherein the PEG ester alkyl comprises 10-100 ethylene glycol units. Embodiment 4. A compound of formula 2: [ka] where R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; and Ac is an acetyl group. Embodiment 5. R2 is C 12 Alkyl, C 18 Alkenyl, C 20 Alkenyl, or C 22 The compound of embodiment 4, wherein the compound is alkenyl. Embodiment 6. [ka] is a substituted or unsubstituted palmitoyl, oleoyl, linoleoyl, linolenoyl, arachidonoyl, eicosapentaenoyl, or docosahexaenoyl group. Embodiment 7. [ka] The compound of embodiment 4, wherein is a succinate ester of retinol. Embodiment 8. [ka] is an omega-3 fatty acid ester. Embodiment 9. A compound according to embodiment 4, wherein R2 is substituted or unsubstituted phenyl or benzyl. Embodiment 10. A compound according to embodiment 9, wherein R2 is benzyl containing an amino substituent. Embodiment 11. A compound according to embodiment 9, wherein R2 is para-aminobenzyl. Embodiment 12. The compound of embodiment 4, wherein R2 is mycophenolic acid. Embodiment 13. The compound of embodiment 4, wherein R2 is an alkyl PEG ester. Embodiment 14. The compound of embodiment 13, wherein the alkyl PEG ester comprises 10 to 100 ethylene glycol units. Embodiment 15. A compound of formula 3: [ka] where R3 is a substituted or unsubstituted C 1-4 Alkyl, C 2-4 C optionally substituted with alkenyl or protected or free amine 1-3 is an alkyl carboxylate, Or, R3 is (i) a hydroxyl group and (ii) [ka] and Ac is an acetyl group. Embodiment 16. A compound of formula 3 [ka] or The compound according to embodiment 12, which is a mixture thereof. Embodiment 17. R3 is unsubstituted C 1-4 The compound of embodiment 12 or 13, wherein is alkyl. Embodiment 18. R3 is C 2 The compound of embodiment 12 or 13, wherein the compound is alkenyl. Embodiment 19. C in which R3 is substituted with a Boc-protected amine 1-3 The compound of embodiment 12 or 13, wherein is alkyl. Embodiment 20. C in which R3 is substituted with an N-Boc protected glutamate or aspartate 1-3The compound of embodiment 12 or 13, wherein is alkyl. In embodiment 21.R3 [ka] C replaced with 3 The compound of embodiment 12 or 13, wherein is alkyl. Embodiment 22. A compound of formula 3: [ka] 16. The compound of embodiment 15, wherein Embodiment 23. A compound of formula 4: B-R1-B' (Formula 4) where B and B' are independently H or [ka] and where B and B' are not both H, and: When either B or B' is H, R1 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, or alkenylaryl; or When B and B' are not both H, R1 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, PEG ester alkyl, or protected or free amine 1-3 is an alkyl carboxylate; R4 is a nucleobase; and Ac is an acetyl group. Embodiment 24. A compound according to embodiment 23, wherein R1 is an alkyl PEG ester. Embodiment 25. The compound of embodiment 23, wherein the PEG ester alkyl contains 10 to 100 ethylene glycol units. Embodiment 26. A compound of formula 5: C-R1-C' (Formula 5) where C and C' are independently H or [ka] and where C and C' are not both H, and: If one of C or C' is H, R1 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, or alkenylaryl; or When C and C' are not both H, R1 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, PEG ester alkyl, or protected or free amine 1-3 is an alkyl carboxylate; R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group. Embodiment 27. A compound according to embodiment 26, wherein R1 is an alkyl PEG ester. Embodiment 28. The compound of embodiment 26, wherein the PEG ester alkyl contains 10 to 100 ethylene glycol units. Embodiment 29. A compound of formula 6: [ka] where R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; R4 is a nucleobase; and Ac is an acetyl group. 30. R2 is C 12 Alkyl, C 18 Alkenyl, C 20 Alkenyl, or C 22 The compound of embodiment 29, wherein the compound is alkenyl. EMBODIMENT 31. [ka] The compound of embodiment 30, wherein is a substituted or unsubstituted palmitoyl, oleoyl, linoleoyl, linolenoyl, arachidonoyl, eicosapentaenoyl, or docosahexaenoyl group. EMBODIMENT 32. [ka] The compound of embodiment 29, wherein is a succinate ester of retinol. EMBODIMENT 33. [ka] is an omega-3 fatty acid ester. Embodiment 34. A compound according to embodiment 29, wherein R2 is substituted or unsubstituted phenyl or benzyl. Embodiment 35. A compound according to embodiment 34, wherein R2 is benzyl containing an amino substituent. Embodiment 36. A compound according to embodiment 34, wherein R2 is para-aminobenzyl. Embodiment 37. A compound according to embodiment 29, wherein R2 is mycophenolic acid. Embodiment 38. A compound according to embodiment 29, wherein R2 is an alkyl PEG ester. Embodiment 39. The compound of embodiment 38, wherein the alkyl PEG ester contains 10 to 100 ethylene glycol units. Embodiment 40. A compound of formula 7: [ka] where R2 is a substituted or unsubstituted C 8-24 Alkyl, C 8-24 alkenyl, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group. Embodiment 41. R2 is C 12 Alkyl, C 18 Alkenyl, C 20 Alkenyl, or C 22 The compound of embodiment 40, wherein the compound is alkenyl. EMBODIMENT 42. [ka] is a substituted or unsubstituted palmitoyl, oleoyl, linoleoyl, linolenoyl, arachidonoyl, eicosapentaenoyl, or docosahexaenoyl group. EMBODIMENT 43. [ka] The compound of embodiment 40, wherein is a succinate ester of retinol. EMBODIMENT 44. [ka] is an omega-3 fatty acid ester. Embodiment 45. A compound according to embodiment 41, wherein R2 is substituted or unsubstituted phenyl or benzyl. Embodiment 46. A compound according to embodiment 45, wherein R2 is benzyl containing an amino substituent. Embodiment 47. A compound according to embodiment 45, wherein R2 is paraaminobenzyl. Embodiment 48. A compound according to embodiment 40, wherein R2 is mycophenolic acid. Embodiment 49. A compound according to embodiment 40, wherein R2 is an alkyl PEG ester. Embodiment 50. The compound of embodiment 49, wherein the alkyl PEG ester contains 10 to 100 ethylene glycol units. Embodiment 51. A compound of formula 8: [ka] where R3 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4 C optionally substituted with alkenyl, or protected or free amine 1-3 Is it an alkyl group? or R3 is (i) a hydroxyl group and (ii) [ka] contains a carbon bonded to one of the R4, R4', and R4" are each independently a nucleobase; and Ac is an acetyl group. Embodiment 52. R3 is unsubstituted C 1-4 The compound of embodiment 51, wherein said compound is alkyl. 53. R3 is C 2 The compound of embodiment 51, wherein the compound is alkenyl. Embodiment 54. R3 is a C substituted with a Boc-protected amine. 1-3 The compound of embodiment 51, wherein said compound is alkyl. Embodiment 55. R3 is a C substituted with an N-Boc protected glutamic or aspartic acid. 1-3 The compound of embodiment 51, wherein said compound is alkyl. In embodiment 56.R3 [ka] C replaced with 3 The compound of embodiment 51, wherein said compound is alkyl. Embodiment 57. The compound of formula 8 is [ka] The compound of embodiment 51, wherein Embodiment 58. A compound of formula 9: [ka] where R3 is a substituted or unsubstituted C 1-4 Alkyl, C 1-4C optionally substituted with alkenyl, or protected or free amine 1-3 Is it an alkyl group? or where R3 is (i) a hydroxyl group and (ii) [ka] is a carbon bonded to one of the wherein R, R', and R" are each independently nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group. Embodiment 59. R3 is unsubstituted C 1-4 The compound of embodiment 58, wherein said compound is alkyl. 60. R3 is C 2 The compound of embodiment 58, wherein the compound is alkenyl. Embodiment 61. C in which R3 is substituted with a Boc-protected amine 1-3 The compound of embodiment 58, wherein said compound is alkyl. Embodiment 62. A C 11 compound in which R3 is replaced with an N-Boc protected glutamic or aspartic acid 1-3 The compound of embodiment 58, wherein said compound is alkyl. Embodiment 63. R3 is [ka] C replaced with 3 The compound of embodiment 58, wherein said compound is alkyl. Embodiment 64. A compound of formula 9: [ka] 59. The compound of embodiment 58, wherein Embodiment 65. A method for making a compound of Formula 1, Formula 2, or Formula 3, comprising the steps of: (a) adding a protecting group to the 5'-carbon of D-ribose to form a 5'-protected ribose; (b) acetylating the hydroxyl groups at the 1', 2', and 3' carbons of the 5'-protected ribose to form an acetylated 5'-protected ribose; (c) deprotecting the 5'-carbon of the acetylated 5'-protected ribose to form an acetylated 5'-deprotected ribose; and (d) coupling the acetylated 5'-deprotected ribose with a reactant containing R1, R2, and / or R3 to form a compound of Formula 1, Formula 2, or Formula 3. Embodiment 66 The method of embodiment 65, wherein the coupling is carried out by a mechanochemical reaction. Embodiment 67. The method of embodiment 65 or 66, wherein the reactant in (d) comprises an acid chloride, an acid anhydride, a dicarboxylic acid, a monocarboxylic acid, or a combination thereof. Embodiment 68. A method of making a compound of formula 4, formula 5, or formula 6, comprising reacting a compound of formula 1, formula 2, or formula 3 with a functionalized nucleobase to form a compound of formula 4, formula 5, or formula 6. Embodiment 69. A method of making a compound of formula 7, formula 8, or formula 9, comprising reacting a compound of formula 1, formula 2, or formula 3 with a functionalized nicotinamide to form a compound of formula 4, formula 5, or formula 6. Embodiment 70. The method of embodiment 68 or 69, wherein the reaction is carried out by a mechanochemical reaction. Embodiment 71. A composition comprising a compound according to any one of embodiments 1 to 64 and a pharma- ceutically acceptable excipient. Embodiment 72. A method of treating nicotinamide adenine dinucleotide (NAD) deficiency in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 26-28, any one of embodiments 40-50, or any one of embodiments 58-64. Embodiment 73. A method of increasing nicotinamide adenine dinucleotide (NAD) in a subject in need thereof, comprising administering to said subject a compound of any one of embodiments 26-28, any one of embodiments 40-50, or any one of embodiments 58-64. Embodiment 74. The method of embodiment 72 or 73, further comprising administering pterostilbene to the subject. EXAMPLES

[0132] Example 1. Synthesis Scheme 1 An exemplary synthetic method is shown below in this example as Synthetic Scheme 1. Synthetic Scheme 1 : [ka]

[0133] Synthesis of compound 2 A round bottom flask was charged with D-ribose followed by pyridine at room temperature under nitrogen atmosphere. To this solution, trityl chloride was added and the resulting solution was stirred at room temperature overnight (16 hours). The reaction mixture was then quenched with methanol and stirred for 5-10 minutes. The resulting mixture was evaporated under reduced pressure to remove pyridine and give a pale yellow syrupy residue which was treated with DCM and DI water. The organic layer was collected and washed with brine and diluted with NaCl. 2 SO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give the desired compound as a pale yellow syrup. See, e.g., Kristinsson et al., “A novel synthesis of sulfamoyl nucleosides,” Tetrahedron 50 (23): 6825-6838 (1994).

[0134] 1 H NMR (400 MHz, CDCl 3 ), δ, ppm: 3.06 (dd, 1H, 1H'), 3.23 (dd, 1H, 1H'), 3.96 (m, 1H, 4H'), 4.15 (m, 2H, 3H',2H'), 5.33 (d, 1H, 1H'), 7.21 (m, 9H), 7.38 (M, 6H). 13 CNMR (101 MHz, CDCl 3), δ, ppm: 64.0, 71.9, 72.1, 82.8, 87.3, 96.8, 127.8, 128.08, 143.4.

[0135] Synthesis of compound 3 A clean and dry round bottom flask was charged with intermediate 2 and toluene. The reaction mixture was then cooled on ice, acetic anhydride was added, and triethylamine was slowly added. The reaction mixture was then warmed to room temperature and stirred at the same temperature overnight (16 hours). The progress of the reaction mixture was monitored by TLC, and after the reaction was completed, the reaction mixture was diluted with DI water and toluene and stirred well. The organic layer was collected and washed with brine and added with NaCl. 2 SO 4 The mixture was dried at 40° C. and evaporated under reduced pressure to give the desired compound as a colorless syrup. See, e.g., Kristinsson et al., Tetrahedron 50 (23): 6825-6838 (1994).

[0136] 1 H NMR (400 MHz, CDCl 3 ), δ, ppm: 1.90 (s, 3H), 1.92 (s, 3H), 2.03 (s, 3H), 3.07-3.11 (dd, 1H, J= 4.2, 10.4 Hz), 3.26-3.3 (dd, 1H, J= 3.8, 10.3 Hz), 4.24 (m, 1H), 6.12 (brs, 1H), 7.12-7.24 (m, 9H), 7.36-7.38 (m, 6H). 13 CNMR (101 MHz, CDCl 3 ), δ, ppm: 20.4, 20.5, 21.0, 63.2, 70.8, 74.3, 86.7, 98.3, 125.2-128.6 (phenyl carbons), 143.6, 169.3, 169.4, 169.6.

[0137] Synthesis of compound 4 A clean round bottom flask was charged with intermediate 3 and 80% acetic acid was added at room temperature. The resulting mixture was then stirred at room temperature until the starting material disappeared. After the reaction was completed, acetic acid was distilled off under reduced pressure, followed by azeotropic distillation to completely remove acetic acid. The reaction mixture was then diluted with ethyl acetate and subjected to aqueous work-up. The organic layer was collected and washed with brine and added with NaCl. 2 SO 4 The crude compound was dried at 40° C. and evaporated under reduced pressure to give the crude compound as a colorless syrup. The crude compound was purified by column chromatography (Teledyne) using a mixture of hexane and ethyl acetate. The desired compound was obtained in 40-50% ethyl acetate in hexane. See, e.g., Winzar et al., “A Simple Synthesis of C-8 Modified 2-Keto-3-deoxy-D-manno-octulosonic Acid (KDO) Derivatives,” Synlett 2010 (4): 583-586 (2010).

[0138] The specific procedure involves stirring a mixture of intermediate 3 in 80% acetic acid for 3-4 days. A white solid of trityl alcohol is precipitated and removed by filtration, and the filtrate is evaporated and purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired material as a colorless syrup.

[0139] 1 H NMR (400 MHz, CDCl 3 ), δ, ppm: 2.07 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 3.64-3.68 (dd, 1H), 3.84-3.88 (dd, 1H), 4.24-4.27 (m, 1H), 5.34-5.36 (m, 1H), 5.39-5.42 (m, 1H), 6.16 (brs, 1H). 13 C NMR (100 MHz, CDCl 3) ppm : -20.4, 20.6, 20.9, 61.81, 69.9, 74.4, 82.3, 98.1, 169.4, 169.9, 171.1. HRMS found: 297.0738; Calculated for C 11 H 16 O 8 (M+Na): 299.0743. Exemplary spectra are shown in Figures 1A-1C.

[0140] General synthesis of compound 6(ah) A ball mill jar was charged with intermediate 4 (2 equiv.), followed by compound 5(ah) (1 equiv.), EDC (2 equiv.), catalytic DMAP (0.2 equiv.), and dichloromethane (2-3 drops). The resulting contents were ball milled in a Retsch MM400 mill for 30-60 min at 30 Hz. The reaction mixture was then dissolved in a flask using dichloromethane for aqueous workup. The organic layer was washed with brine and NaCl. 2 SO 4 The reaction was dried at 40° C. and evaporated under reduced pressure to give the crude compound as a colorless syrup. The reaction was monitored by TLC.

[0141] The crude compound obtained was 1 The compound was analyzed by H NMR and matched standard NMR. Exemplary spectra are shown in Figures 22A-22G. The resulting compound was judged to be pure and was carried forward to the next step without further purification. Alternatively, the compound was purified by column chromatography (Teledyne) using a mixture of hexane and ethyl acetate.

[0142] Acid anhydrides may also be used in place of the corresponding acids to give the desired products.

[0143] General synthesis of compound 7 A clean, dry round-bottom flask was charged with nicotinamide, followed by HMDS, and the resulting mixture was heated to 110-200 °C for 16 h. The reaction mixture was then distilled and used directly in the next step without further purification. See, e.g., Makarov et al., “Scalable syntheses of traceable ribosylated NAD+ precursors,” Org Biomol Chem. 17: 8716-8720 (2019).

[0144] General synthesis of compound 8(ah) A ball mill jar was charged with the corresponding intermediate 6(ah) (1 eq.) and NAM-TMS (compound 7 (2 eq.)), followed by the addition of trimethylsilyl trifluoromethanesulfonate and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled for 20-30 min at 30 Hz in a Retsch MM400 mill, depending on the mono- or diester derivative. The progress of the reaction was monitored. 1 The reaction was monitored by H NMR. After the reaction was completed, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried under high vacuum to give a yellow foamy, highly hygroscopic mixture.

[0145] General synthesis of compound 9(ah) A clean, dry round-bottom flask was charged under nitrogen with the corresponding NR ester 8(ah), followed by the addition of a minimal amount of degassed DI water to dissolve the compound. To this solution was added solid NaHCO 3 Add Na 2 S 2 O 4 was added in small portions and the resulting solution was stirred at room temperature for 1-2 min. Degassed ethyl acetate was then added and the resulting mixture was stirred at room temperature for 4 h, followed by an aqueous workup using DI water and ethyl acetate. The aqueous layer was extracted twice with degassed ethyl acetate and the organic layers were combined, dried and evaporated under reduced pressure to give the desired compound. General anion exchange protocol from NR triflate (NR-OTf) to NR chloride (NR-Cl)

[0146] The clear solution of NR triflate in DI water was cooled on ice to 0-5 °C and stirred for 15-20 min. Amberlite resin was added to this solution and stirred at 0-5 °C for 2 h. A glass column was packed with Amberlite resin, to which DI water was added and the column was equilibrated with DI water. The stirred solution of NR triflate and Amberlite resin was added to the column and eluted with DI water or a 1:1 mixture of water and acetonitrile. The collected fractions were tested for chloride ions by titration with silver nitrate solution. The desired fractions from the column were combined and evaporated under reduced pressure to obtain a white powder of NR chloride. The resulting product was 1 HNMR and 19 FNMR analysis was used to test for the completion of the triflate to chloride ion exchange. 19 The absence of fluorine peaks in FNMR confirmed the complete conversion of the corresponding triflate salt to the chloride. The synthesis of compound 10(ah) is further described in Example 5.

[0147] Example 2. Synthesis of compound 6(ah) This example provides an exemplary synthesis method for compound 6(ah) of Synthetic Scheme 1 shown in Example 1. The structure of compound 6(ah) is shown below. [ka]

[0148] Synthesis of compound 6a (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (100 mg, 0.37 mmol) and malonic acid (20 mg, 0.18 mmol), followed by DCC (77 mg, 0.37 mmol), DMAP catalyst, and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill at 30 Hz for 80 min. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The precipitated white solid was filtered and the resulting crude compound was then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0149] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.07 (s, 3H), 2.1 (s, 3H), 2.13 (s, 3H), 3.45 (s, 2H), 4.23-4.27 (m, 2H, H5'), 4.37-4.43 (m, 2H, H5'), 4.39 (m, 2H, H4'), 5.32 (m, 2H, H3'), 5.33 (m, 2H, H2'), 6.15 (brd, 2H, H1'). 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.3, 20.4, 20.9, 40.9, 64.8, 70.4, 74.0, 79.0, 98.1, 165.5, 168.9, 169.3, 169.6; MS: found m / z = 643.04 (M+Na). Calculated for C 25 H 32 O 18 (M+1): 621.1667; 643.14 (M+Na). Exemplary spectra are shown in Figures 2A-C.

[0150] Synthesis of compound 6a (g scale) A ball mill jar was charged with intermediate 4 (1 g, 3.76 mmol, 2 equiv.), followed by malonic acid (200 mg, 1.88 mmol, 1 equiv.), DCC (755 mg, 3.76 mmol, 2 equiv.), catalytic DMAP (45 mg, 0.37 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill at 30 Hz for 60 min. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane (DCM). The crude compound in DCM was cooled at 4 °C for 30 min and the DCU impurity was filtered. The resulting solution was diluted with water followed by aqueous workup. The organic layer was separated and washed with 10% CuSO 4 The resulting organic layer was washed with Na 2 SO 4 The crude compound was obtained as a mixture of diastereomers containing 16% α and 84% β isomers (960 mg, yield: 82%) after drying at 4°C and evaporation under reduced pressure.

[0151] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.07 (s, 3H), 2.1 (s, 3H), 2.13 (s, 3H), 3.45 (s, 2H), 4.23-4.27 (m, 2H, H5'), 4.37-4.43 (m, 2H, H5'), 4.39 (m, 2H, H4'), 5.32 (m, 2H, H3'), 5.33 (m, 2H, H2'), 6.15 (brd, 2H, HF). 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.3, 20.4, 20.9, 40.9, 64.8, 70.4, 74.0, 79.0, 98.1, 165.5, 168.9, 169.3, 169.6; MS: found m / z = 643.04 (M+Na). Calculated for C 25 H 32 O 18 (M+l): 621.1667; 643.14 (M+Na).

[0152] Synthesis of compound 6b (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with the intermediate (130 mg, 0.49 mmol) and succinic acid (25 mg, 0.24 mmol), followed by EDCI (95.7 mg, 0.49 mmol), DMAP (6 mg, 0.049 mmol) and 2-3 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill at 30 Hz for 30 min. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The resulting mixture was evaporated under reduced pressure and then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0153] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.07 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.68 (brs, 4H), 4.17-4.21 (dd, 2H, 5H'), 4.32-4.36 (dd, 2H, 5H'), 4.36-4.38 (m, 2H, 4H'), 5.32 (m, 2H, 3'H), 5.33 (m, 2H, 2'H), 6.16 (brd, 2H, 1'H); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.4, 20.46, 21, 28.7, 64, 70.4, 74, 79.1, 98.1, 168.9, 169.3, 169.6, 171.5; MS: found m / z = 652.07 (M+H 2 O); 657.01 (M+Na). HRMS found: 652.2085. Calculated for C 26 H 34 O 18 (M+H 2 O): 652.1851. Exemplary spectra are shown in Figures 3A-3C.

[0154] Synthesis of compound 6b (g scale) A ball mill jar was charged with intermediate 4 (1.1 g, 3.99 mmol, 2 equiv.), followed by succinic anhydride (200 mg, 1.99 mmol, 1 equiv.), EDCI (765 mg, 3.99 mmol, 2 equiv.), catalytic DMAP (49 mg, 0.4 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill at 30 Hz for 60 min. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane (DCM) and diluted with water for further aqueous workup. The organic layer was separated and washed with 10% CuSO 4 The resulting organic layer was then washed with Na 2 SO 4 The crude compound was obtained as a mixture of diastereomers containing 11% α and 89% β isomers after drying at 40° C. and evaporation under reduced pressure to give the crude compound as an amber syrup (1.2 g, yield: 95%).

[0155] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.07 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.68 (brs, 4H), 4.17-4.21 (dd, 2H, 5H'), 4.32-4.36 (dd, 2H, 5H'), 4.36-4.38 (m, 2H, 4H'), 5.32 (m, 2H, 3'H), 5.33 (m, 2H, 2'H), 6.16 (brd, 2H, 1'H); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.4, 20.46, 21, 28.7, 64, 70.4, 74, 79.1, 98.1, 168.9, 169.3, 169.6, 171.5; MS: found m / z = 652.07 (M+H 2 O); 657.01 (M+Na). HRMS found: 652.2085. Calculated for C 26 H 34 O 18(M+H 2 O): 652.1851.

[0156] Synthesis of compound 6c (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (100 mg, 0.36 mmol), and glutaric acid (25 mg, 0.18 mmol), followed by DCC (74 mg, 0.36 mmol), DMAP (catalytic amount), and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill for 80 min at 30 Hz. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The precipitated white solid was filtered and the resulting mixture was evaporated under reduced pressure and then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0157] 1 H NMR (400 MHz, CDCl 3 ) ppm: 1.80-1.85 (m, 2H), 1.92 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 2.25 -2.3 (m, 4H), 4.01-4.09 (dd, 2H, 5H'), 4.14-4.2 (dd, 2H, 5H'), 4.22 (m, 2H, 4H'), 5.17 (m, 2H, 3H'), 5.19 (m, 2H, 2H'), 6.02 (brd, 2H, 1H'); 13 C NMR (100 MHz, CDCl 3 ) ppm: 19.6, 20.3, 20.4, 20.9, 32.7, 63.7, 70.4, 74.0, 79.2, 98.1, 168.9, 169.3, 169.6, 172.2; MS: found m / z = 671.04 (M+Na). Calculated for C 27 H 36 O 18 : 650.2058 (M+l); 671.17 (M+Na). Exemplary spectra are shown in Figures 4A-C.

[0158] Synthesis of compound 6c (g scale) A ball mill jar was charged with intermediate 4 (1 g, 3.6 mmol, 2 equiv.), followed by glutaric acid (250 mg, 1.8 mmol, 1 equiv.), DCC (742 mg, 3.6 mmol, 2 equiv.), catalytic DMAP (44 mg, 0.36 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill at 30 Hz for 60 min. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane. The crude compound in DCM was cooled at 4 °C for 30 min and the DCU impurity was filtered. The resulting solution was diluted with water followed by aqueous workup. The organic layer was separated and washed with 10% CuSO 4 The resulting organic layer was then washed with Na 2 SO 4 The crude compound was obtained as a mixture of diastereomers containing 13% α and 87% β isomers after drying at 40° C. and evaporation under reduced pressure to give the crude compound as a pale yellow syrup (1 g, yield: 84%).

[0159] 1 H NMR (400 MHz, CDCl 3 ) ppm: 1.80-1.85 (m, 2H), 1.92 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 2.25 -2.3 (m, 4H), 4.01-4.09 (dd, 2H, 5H'), 4.14-4.2 (dd, 2H, 5H'), 4.22 (m, 2H, 4H'), 5.17 (m, 2H, 3H'), 5.19 (m, 2H, 2H'), 6.02 (brd, 2H, 1H'); 13 C NMR (100 MHz, CDCl 3 ) ppm: 19.6, 20.3, 20.4, 20.9, 32.7, 63.7, 70.4, 74.0, 79.2, 98.1, 168.9, 169.3, 169.6, 172.2; MS: found m / z = 671.04 (M+Na). Calculated for C 27 H36 O 18 : 650.2058 (M+l); 671.17(M+Na).

[0160] Synthesis of compound 6d (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (95 mg, 0.34 mmol) and adipic acid (25 mg, 0.17 mmol), followed by EDCI (65 mg, 0.34 mmol), DMAP (catalytic amount), and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill for 80 min at 30 Hz. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane and further subjected to aqueous workup using DI water and dichloromethane. The organic layer was collected, washed with brine, dried and evaporated under reduced pressure. The resulting crude compound was then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0161] 1 H NMR (400 MHz, CDCl 3 ) ppm: 1.67 (m, 4H), 2.07 (s, 3H), 2.1 (s, 3H), 2.13 (s, 3H), 2.37 (m, 4H), 4.15-4.19 (dd, 2H, 5H'), 4.29-4.33 (dd, 2H, 5H'), 4.34-4.49 (m, 2H, 4H'), 5.31 (m, 2H, 3H'), 5.34 (m, 2H, 2H'), 6.40 (d, 2H); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.3, 20.4, 20.9, 24.0, 33.4, 63.6, 70.5, 74.0, 79.2, 98.1, 168.9, 169.3, 169.5, 172.6; MS: found m / z = 685.14 (M+Na). Calculated for C 28 H 38 O 18: 664.2215 (M+1), 685.19 (M+Na). Exemplary spectra are shown in Figures 5A-5C.

[0162] Synthesis of compound 6d (g scale) A ball mill jar was charged with intermediate 4 (1 g, 3.6 mmol, 2 equiv.), followed by adipic acid (263 mg, 1.8 mmol, 1 equiv.), EDCI (694 mg, 3.62 mmol, 2 equiv.), catalytic DMAP (44 mg, 0.36 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill for 60 min at 30 Hz. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane (DCM) and diluted with water for further aqueous workup. The organic layer was separated and washed with 10% CuSO 4 The resulting organic layer was then washed with Na 2 SO 4 The crude compound was obtained as a mixture of diastereomers containing 9% α and 91% β isomers after drying at 40° C. and evaporation under reduced pressure to give the crude compound as an amber syrup (1.2 g, yield: 90%).

[0163] 1 H NMR (400 MHz, CDCl 3 ) ppm: 1.67 (m, 4H), 2.07 (s, 3H), 2.1 (s, 3H), 2.13 (s, 3H), 2.37 (m, 4H), 4.15-4.19 (dd, 2H, 5H'), 4.29-4.33 (dd, 2H, 5H'), 4.34-4.49 (m, 2H, 4H'), 5.31 (m, 2H, 3H'), 5.34 (m, 2H, 2H'), 6.40 (d, 2H); 13 C NMR (100 MHz, CDCl 3) ppm: 20.3, 20.4, 20.9, 24.0, 33.4, 63.6, 70.5, 74.0, 79.2, 98.1, 168.9, 169.3, 169.5, 172.6; MS: found m / z = 685.14 (M+Na). Calculated for C 28 H 38 O 18 : 664.2215 (M+l), 685.19 (M+Na).

[0164] Synthesis of compound 6e-bis[[(2R,3R,4R,5S)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl]2-(tert-butoxycarbonylamino)pentanedioate (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (55 mg, 0.19 mmol), and N-Boc-glutamic acid (25 mg, 0.1 mmol), followed by EDCI (38.3 mg, 0.19 mmol), DMAP (catalytic amount), and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill at 30 Hz for 30 min. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The resulting mixture was evaporated under reduced pressure and then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0165] 1 H NMR (400 MHz, CDCl 3 ) ppm: 1.4 (s, 9H), 2.07(s, 6H), 2.03-2.04 (m, 2H), 2.10-2.13 (brs, 12H), 2.45-2.48 (t, 2H), 4.10-4.18 (m, 2H), 4.28-4.37 (m, 6H), 5.31-5.34 (m, 4H), 6.15 (brd, 2H); 13 C NMR (100 MHz, CDCl 3) ppm: 20.3, 20.4, 20.9, 27.4, 28.2, 29.7, 64.0, 64.5, 70.4, 70.5, 74.06, 74.1, 79.1, 79.2, 98.0, 98.1, 168.9, 169.3, 169.6, 172.1. MS: found m / z = 786.08 (M+Na). HRMS found: 786.2435; Calculated for C 32 H 45 NO 20 : 765.2691 (M+l); 786.2433 (M+Na). Exemplary spectra are shown in Figures 6A-6C.

[0166] Synthesis of compound 6e (g scale) A ball mill jar was charged with intermediate 4 (1 g, 3.62 mmol, 2 equiv.), followed by N-Boc-glutaric acid (447 mg, 1.81 mmol, 1 equiv.), EDCI (693 mg, 3.62 mmol, 2 equiv.), catalytic DMAP (45 mg, 0.36 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill for 60 min at 30 Hz. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane (DCM) and diluted with water for further aqueous workup. The organic layer was separated and washed with 10% CuSO 4 The resulting organic layer was then washed with Na 2 SO 4 The crude compound was obtained as a mixture of diastereomers containing 9% α and 91% β isomers after drying at 40° C. and evaporation under reduced pressure to give the crude compound as an amber syrup (1.2 g, yield: 88%).

[0167] 1 H NMR (400 MHz, CDCl 3) ppm: 1.4 (s, 9H), 2.07(s, 6H), 2.03-2.04 (m, 2H), 2.10-2.13 (brs, 12H), 2.45-2.48 (t, 2H), 4.10-4.18 (m, 2H), 4.28-4.37 (m, 6H), 5.31-5.34 (m, 4H), 6.15 (brd, 2H); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.3, 20.4, 20.9, 27.4, 28.2, 29.7, 64.0, 64.5, 70.4, 70.5, 74.06, 74.1, 79.1, 79.2, 98.0, 98.1, 168.9, 169.3, 169.6, 172.1. MS: found m / z = 786.08 (M+Na). HRMS found: 786.2435; Calculated for C 32 H 45 NO 20 : 765.2691 (M+l); 786.2433 (M+Na).

[0168] Synthesis of compound 6f-bis[[(2R,3R,4R,5S)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl](E)-but-2-enedioate (mg scale) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (47 mg, 0.17 mmol) and fumaric acid (10 mg, 0.08 mmol), followed by EDCI (33 mg, 0.172 mmol), DMAP (catalytic amount, 0.01 mmol), and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill for 30 min at 30 Hz. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane, followed by aqueous workup using DI water and dichloromethane. The organic layer was collected, washed with brine, dried, and evaporated under reduced pressure. The resulting crude compound was then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0169] 1H NMR (400 MHz, CDCl 3 ) ppm: 2.06 (s, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 4.26-4.30 (dd, 2H, 5H'), 4.39 -4.40 (m, 2H, 4H'), 4.40 -4.41 (dd, 2H, 5H'), 5.35 (m, 2H, 3H'), 5.37 (m, 2H, 2H'), 6.16 (s, 2H, 1H'), 7.28 (d, 2H, olefinic Hs, J= 13.5 Hz); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.4, 20.4, 21.0, 64.3, 70.3, 74.0, 78.9, 98.1, 133.5, 164.0, 168.9, 169.3, 169.6; MS: found m / z = 678.29 (M+Na). HRMS found: 657.1635 Calculated for C 26 H 32 O 18 : 634.1745 (M+l), 655.1486 (M+Na). Exemplary spectra are shown in Figures 7A-7C.

[0170] Synthesis of compound 6f (g scale) A ball mill jar was charged with intermediate 4 (1 g, 3.62 mmol, 2 equiv.), followed by fumaric acid (208 mg, 1.81 mmol, 1 equiv.), EDCI (695 mg, 3.62 mmol, 2 equiv.), catalytic DMAP (44 mg, 0.36 mmol, 0.2 equiv.), and dichloromethane (300 μL). The resulting contents were ball milled in a Retsch MM400 mill at 30 Hz for 60 min. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane, followed by aqueous workup. The organic layer was washed with brine and NaCl. 2 SO 4Drying at 40° C. and evaporation under reduced pressure gave the crude compound as a colorless syrup, which was finally purified by column chromatography (Teledyne) using a mixture of hexane and ethyl acetate. The pure compound was obtained as a colorless syrup (550 mg, 48.6% yield). The crude compound was obtained as a mixture of diastereomers containing 8% α and 92% β isomers.

[0171] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.06 (s, 3H), 2.08 (s, 3H), 2.14 (s, 3H), 4.26-4.30 (dd, 2H, 5H'), 4.39 -4.40 (m, 2H, 4H'), 4.40 -4.41 (dd, 2H, 5H'), 5.35 (m, 2H, 3H'), 5.37 (m, 2H, 2H'), 6.16 (s, 2H, 1H'), 7.28 (d, 2H, olefinic Hs, J= 13.5 Hz); 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.4, 20.4, 21.0, 64.3, 70.3, 74.0, 78.9, 98.1, 133.5, 164.0, 168.9, 169.3, 169.6; MS: found m / z = 678.29 (M+Na). HRMS found: 657.1635 Calculated for C 26 H 32 O 18 : 634.1745 (M+l), 655.1486 (M+Na).

[0172] Synthesis of compound 6g - [(2R,3R,4R,5S)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl tridecanoate (Protocol 1) A stainless steel ball mill jar (1.5 ml) was charged with intermediate 4 (200 mg, 0.72 mmol) and lauric acid (145 mg, 0.72 mmol), followed by EDCI (207 mg, 1.08 mmol), DMAP catalyst, and anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill for 30 min at 30 Hz. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The resulting mixture was evaporated under reduced pressure and then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired intermediate.

[0173] 1 H NMR (400 MHz, CDCl 3 ) ppm: 0.87 (t, 3H, J= 6.7 HZ), 1.28 (m, 16H), 1.62 (m, 2H), 2.07 (s, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.33 (t, 2H, 7.5 Hz), 4.1-4.32 (dd, 2H, 5H'), 4.38 (m, 1H, 4H'), 5.32 (m, 1H, 3H'), 5.34 (m, 1H, 2H'), 6.16 (d, 1H, 1H'); 13 C NMR (100 MHz, CDCl 3 ) ppm: 14.1, 20.3, 20.3, 20.9, 22.5, 24.7, 29.0, 29.1, 29.2, 29.3, 29.4, 31.8, 33.9, 63.3, 70.5, 74.0, 79.2, 98.1, 168.8, 169.3, 169.5, 173.1; MS: found m / z = 481.19 (M+Na). HRMS found: 481.2401; Calculated for C 24 H 40 O 9 : 460.2672 (M+l); 481.2414 (M+Na). Exemplary spectra are shown in Figures 8A-C.

[0174] Synthesis of compound 6g (Protocol 2) A ball mill jar was charged with intermediate 4 (1 equiv.), followed by lauric acid (1 equiv.), EDCI (1 equiv.), catalytic DMAP (0.2 equiv.), and dichloromethane (2-3 drops). The resulting contents were ball milled in a Retsch MM400 mill at 30 Hz for 45 min. The progress of the reaction was monitored by TLC. The reaction mixture was then dissolved in a flask using dichloromethane, followed by aqueous workup. The organic layer was washed with brine and NaCl. 2 SO 4 The crude compound was dried at 40° C. and evaporated under reduced pressure to give a colorless syrup, which was finally purified by column chromatography (Teledyne) using a mixture of hexane and ethyl acetate. An exemplary spectrum is shown in FIG. 22G.

[0175] 1 H NMR (400 MHz, CDCl 3 ) ppm: 0.87 (t, 3H, J= 6.7 HZ), 1.28 (m, 16H), 1.62 (m, 2H), 2.07 (s, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 2.33 (t, 2H, 7.5 Hz), 4.1-4.32 (dd, 2H, 5H'), 4.38 (m, 1H, 4H'), 5.32 (m, 1H, 3H'), 5.34 (m, 1H, 2H'), 6.16 (d, 1H, 1H'); 13 C NMR (100 MHz, CDCl 3 ) ppm: 14.1, 20.3, 20.3, 20.9, 22.5, 24.7, 29.0, 29.1, 29.2, 29.3, 29.4, 31.8, 33.9, 63.3, 70.5, 74.0, 79.2, 98.1, 168.8, 169.3, 169.5, 173.1; MS: found m / z = 481.19 (M+Na). HRMS found: 481.2401; Calculated for C 24 H 40 O 9 : 460.2672 (M+l); 481.2414 (M+Na).

[0176] Synthesis of compound 6h A clean, dry ball mill jar was charged with intermediate 4 (200 mg, 0.72 mmol), mycophenolic acid (232 mg, 0.72 mmol), followed by DCC (148 mg, 0.72 mmol), DMAP (catalytic amount), and 1-2 drops of anhydrous dichloromethane. The contents were ball milled in a Retsch MM400 mill for 60 min at 30 Hz. The jar was cooled to room temperature and the contents were dissolved in a flask using dichloromethane. The precipitated white solid was filtered and the resulting mixture was evaporated under reduced pressure and then purified by Teledyne column chromatography using a mixture of ethyl acetate and hexane to give the desired compound.

[0177] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.05 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 2.27 - 2.31 (br m, 2H), 2.39-2.47 (br m, 2H), 3.36 (d, 2h, J= 6.8 Hz), 3.74 (s, 3H), 4.07-4.11 (dd, 1H, 5H'), 4.23-4.27 (dd, 1H, 5H'), 4.3-4.34 (m, 1H, 4H'), 5.22 (m, 1H, 3H'), 5.22 (s, 2H, lactone 2H), 5.31 (m, 1H, 3H'), 5.32 (m, 1H, olefinic H), 6.13 (s, 1H, 1H'); 13 C NMR (100 MHz, CDCl 3 ) ppm: 11.5, 16.0, 20.43, 20.45, 20.9, 22.5, 32.8, 34.3, 53.3, 60.9, 63.5, 70.0, 70.5, 74.1, 79.2, 98.1, 116.6, 122.0, 122.9, 129.4, 133.8, 144.0, 163.6, 168.9, 169.3, 172.7. Exemplary spectra are shown in Figures 9A-B.

[0178] Example 3. Synthesis of compound 8(ah) This example provides an exemplary synthesis method for compound 8(ah) of Synthetic Scheme 1 shown in Example 1. The structure of compound 8(ah) is shown below. [ka]

[0179] Synthesis of compound 8a A ball mill jar was charged with intermediate 8a (70 mg, 0.112 mmol) and compound 7 (43 mg, 0.22 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (81 μL, 0.44 mmol) and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8a as a yellow foamy, highly hygroscopic solid.

[0180] 1 H NMR (400 MHz, Acetone-d6) ppm: 2.01 (s, 6H), 2.02 (s, 3H), 2.07 (s, 3H), 3.85 (s, 2H), 4.54-4.64 (dd, 4H, J= 2.76 Hz, J= 2.44 Hz), 4.83-4.86 (m, 2H), 5.49-5.52 (t, 2H, J= 5.6 Hz), 5.65-5.68 (m, 2H), 6.72 (d, 2H, J= 3.68 Hz), 8.41-8.45 (m, 2H), 9.13-9.2 (m, 2H), 9.39-9.42 (m, 2H), 9.62 (s, 2H); 13C NMR (100 MHz, Acetone-d6) ppm: 19.51, 19.54, 40.48, 62.99, 69.05, 76.11, 82.79, 97.94, 127.86, 128.75, 141.25, 143.18, 145.94, 166.13, 169.34, 169.74. 19 F (376 MHz, Acetone-d6) ppm: - 79.14. Exemplary spectra are shown in Figures 10A-C.

[0181] Synthesis of compound 8b A ball mill jar was charged with intermediate 8b (100 mg, 0.157 mmol) and compound 7 (61 mg, 0.315 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (114 μL, 0.394 mmol) and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8b as a yellow, foamy, highly hygroscopic solid.

[0182] 1 H NMR (400 MHz, Acetone-d6) ppm: 9.61 (s, 2H), 9.41 (m, 2H), 9.14 (m, 2H), 8.43 (t, 2H, J= 14 Hz), 7.99 (brs, -2NH Hs), 6.72 (d, 2H, J= 3.4 Hz), 5.65 (t, 2H, J= 8.8 Hz), 5.44 (t, 2H, J= 5.5 Hz), 4.82-4.83 (m, 2H), 4.51-4.57 (m, 4H), 2.71-2.8 (m, 4H), 1.98-2.07 (s, 12H); 13C NMR (100 MHz, Acetone-d6) ppm: 171.9, 169.6, 169.2, 162.6, 145.9, 142.9, 141.2, 134.7, 128.7, 127.8, 97.9, 82.9, 76.1, 69.0, 65.1, 62.2, 19.5, 14.6. MS: found m / z = 909.08 (M+OTf). HRMS found: 909.1963; Calculated for C 28 H 34 O 13 : 910.2038 (M+OTf). Exemplary spectra are shown in Figures 11A-11C.

[0183] Synthesis of compound 8c A ball mill jar was charged with intermediate 8c (30 mg, 0.04 mmol) and compound 7 (18 mg, 0.09 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (35 μL, 0.185 mmol) and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8c as a yellow, foamy, highly hygroscopic solid.

[0184] 1 H NMR (400 MHz Acetone-d6) ppm: 1.80-1.87 (m, 2H), 2.04 (s, 6H), 2.09 (s, 6H), 2.48-2.54 (m, 4H), 4.47-4.49 (dd, 4H, J= 2.96, J= 2.48 Hz, ) 4.83-4.83 (m, 2H), 5.45-5.48 (t, 2H, J= 5.56 Hz), 5.65-5.68 (m, 2H), 6.72 (d, 2H, J= 3.44 Hz), 8.41-8.45 (m, 2H), 9.13-9.17 (m, 2H), 9.41-9.42 (m, 2H), 9.63 (s, 2H). 13C NMR (100 MHz, Acetone-d6) ppm: 19.5, 19.53, 19.69, 32.38, 62.07, 69.11, 76.25, 83.08, 97.98, 127.85, 128.71, 141.13, 143.03, 145.95, 169.23, 169.68, 172.22. 19 F (376 MHz, Acetone-d6) ppm: - 79.11. Exemplary spectra are shown in Figures 12A-C.

[0185] Synthesis of compound 8d A ball mill jar was charged with intermediate 8d (40 mg, 0.06 mmol) and compound 7 (23.4 mg, 0.12 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (44 μL, 0.24 mmol). The resulting mixture was ball milled in a Retsch MM400 mill for 30 min at 30 Hz. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8d as a highly hygroscopic solid.

[0186] 1 H NMR (400 MHz Acetone-d6) ppm: 1.56-1.61 (m, 4H), 2.05 (s, 6H), 2.10 (s, 6H), 2.41-2.46 (m, 4H), 4.46-4.58 (dd, 4H, J= 2.76 Hz, 2.16 Hz), 4.83-4.85 (m, 2H), 5.46 -5.49 (t, 2H, J= 5.42 Hz), 5.67-5.69 (m, 2H), 6.72 (d, 2H, J= 3.52 Hz), 8.42-8.45 (m, 2H), 9.14-9.21 (m, 2H), 9.41-9.43 (m, 2H), 9.64 (s, 2H); 13C NMR (100 MHz, Acetone-d6) ppm: 19.52, 19.55, 23.83, 32.96, 62.08, 69.21, 76.24, 83.14, 97.92, 127.88, 128.71, 141.06, 143.11, 143.74, 145.82, 146.0, 169.28, 169.69, 172.51. 19 F (376 MHz, Acetone-d6) ppm: - 79.12. Exemplary spectra are shown in Figures 13A-C.

[0187] Synthesis of compound 8e A ball mill jar was charged with intermediate 6e (200 mg, 0.262 mmol) and compound 7 (100 mg, 0.52 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (232 μL, 1.31 mmol). The resulting mixture was ball milled in a Retsch MM400 mill for 40 min at 30 Hz. After 40 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8e as a highly hygroscopic solid.

[0188] 1 H NMR (400 MHz Acetone-d6) ppm: 1.89 (s, 9 H), 1.97 (s, 12H, overlapped), 4.46 (dd, J = 12.9 Hz, J = 2.5 Hz), 4.46 (dd, J = 12.9 Hz, J = 2.5 Hz), 4.54 (m, 1H), 4.55 (dd, J= 12.9 Hz, J= 3.2 Hz), 5.67 (dd, J = 5.4 Hz, J= 3.6 Hz), 6.74 (d, 2H, J= 3.5 Hz), 8.44 (t, 2H, J= 14 Hz), 9.15-9.17 (brm, 2H), 9.43 (m, 2H), 9.66 (brs, 2H). An exemplary spectrum is shown in FIG.

[0189] Synthesis of compound 8f A ball mill jar was charged with intermediate 8f (70 mg, 0.11 mmol) and compound 7 (43 mg, 0.22 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (67 μL, 0.44 mmol) and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8f as a yellow foamy, highly hygroscopic solid.

[0190] 1 H NMR (400 MHz, Acetone-d6) ppm: 2.09 (s, 6H), 2.12 (s, 6H), 4.66-4.8 (dd, 4H, J = 2.92 Hz, 2.04 Hz), 4.96-4.97 (m, 2H), 5.61 (t, 2H, J= 5.76 Hz), 5.73 (m, 2H), 6.81 (d, 2H, J = 3.08 Hz), 6.96 (s, 2H), 8.41-8.47 (m, 2H), 9.12 (m, 2H), 9.46 (m, 2H), 9.61 (s, 2H). 13 C NMR (100 MHz, Acetone-d6) ppm: 19.52, 62.97, 68.71, 76.12, 82.51, 97.81, 128.75, 133.28, 140.86, 143.06, 146.12, 163.97, 169.48, 169.85. 19 F (376 MHz, Acetone-d6) ppm: - 78.97. Exemplary spectra are shown in Figures 15A-C.

[0191] Synthesis of compound 8g (Protocol 1) A ball mill jar was charged with intermediate 6g (70 mg, 0.15 mmol) and compound 7 (33 mg, 0.16 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (42 μL, 0.22 mmol). The resulting mixture was ball milled in a Retsch MM400 mill for 30 min at 30 Hz. After 30 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8g as a highly hygroscopic solid.

[0192] 1 H NMR (400 MHz, Acetone-d6) ppm : 0.80 (t, 3H), 1.12 (m, 18H), 1.50-1.55 (m, 2H), 2.04 (s, 3H), 2.08 (s, 3H), 2.33-2.45 (m, 2H), 4.45-4.59 (dd, 2H, J= 3.22 Hz, J= 2.28 Hz), 4.81 (m, 1H), 5.45 (t, 1H J= 5.44 Hz), 5.65-5.67 (m, 1H), 6.72 (s, 1H, J= 3.68 Hz), 8.40-8.43 (m, 1H), 9.14-9.18 (m, 1H), 9.41-9.42 (m, 1H), 9.64 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) ppm :-13.45, 19.51, 19.54, 19.66, 22.39, 24.54, 29.07, 29.21, 29.27, 29.3, 29.46, 29.65, 31.7, 33.37, 54.07, 62.05, 69.26, 76.18, 83.13, 97.98, 127.93, 128.7, 141.3, 143.07, 146.04, 169.19, 169.62, 172.7. 19 F (376 MHz, Acetone-d6) ppm: - 79.13. Exemplary spectra are shown in Figures 16A-C.

[0193] Synthesis of compound 8g (Protocol 2) A ball mill jar was charged with the corresponding intermediate 6g (1 equiv.), and NAM-TMS (compound 7, (1 equiv.)), followed by trimethylsilyl trifluoromethanesulfonate (2 equiv.), and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. The progress of the reaction was monitored. 1 The reaction was monitored by H NMR. After the reaction was completed, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried under high vacuum to give a yellow foamy, highly hygroscopic mixture.

[0194] Exemplary products prior to column chromatography 1 The H NMR spectrum is shown in Figure 23A. An exemplary product after column chromatography 1 H NMR and 13 The C NMR spectra are shown in Figures 23B and 23C, respectively.

[0195] NR-lauric acid (NRLR) triflate was successfully purified on a multi-milligram scale (30-40 mg) on ​​a conventional silica column using a mixture of dichloromethane (DCM) and acetone. The pure compound (NRLR) was obtained in a 1:1 mixture of DCM and acetone (20 mg, yield: 60%).

[0196] 1H NMR (400 MHz, Acetone-d6) ppm: 9.55 (s, 1H), 9.32 (d, 1H, J= 6.2 Hz), 9.08 (d, 1H, J= 8.1 Hz), 8.33 (dd, 1H, J= 14.2 Hz, 1.3 Hz), 8.2 (s, 1H, -NH), 7.3 (s, 1H, -NH), 6.55 (d, 1H, J= 3.9 Hz), 5.58 (1H, dd, J= 4 Hz), 5.37 (t, 1H, J= 5.4 Hz), 4.73 - 4.75 (br m, 1H), 4.40 -4.48 (1H, dd, J= 3 Hz, 25 Hz), 2.29-233 (m, 2H), 2.07 (s, 3H), 1.96 (s, 3H), 1.43-1.47 (m, 2H), 1.12 (m, 16 H), 0.72 (t, 3H, J= 6.7 Hz); 13 C NMR (400 MHz, Acetone-d6) ppm: 13.42, 19.49, 19.51, 22.37, 31.68, 33.37, 62.09, 69.32, 76.16, 83.14, 97.96, 128.68, 134.76, 141.25, 142.97, 146.03, 162.68, 169.22, 169.63, 172.73.

[0197] Large-scale (>50 mg) column purification (Teledyne) always yielded a mixture of partially deacetylated (2′ or 3′, or both 2′ and 3′) products.

[0198] Synthesis of compound 8h A ball mill jar was charged with intermediate 6h (50 mg, 0.086 mmol) and compound 7 (17 mg, 0.086 mmol), followed by the addition of trimethylsilyl trifluoromethanesulfonate (32 μL, 0.172 mmol). The resulting mixture was ball milled in a Retsch MM400 mill for 25 min at 30 Hz. After 25 min, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, triturated with diethyl ether, and dried to give compound 8h as a highly hygroscopic solid.

[0199] 1 H NMR (400 MHz, Acetone-d6) ppm: 1.7 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.09 (s, 3H), 2.3 (m, 2H), 2.43-2.58 (m, 2H), 3.30-3.32 (m, 2H), 3.72 (s, 3H), 4.1-4.44 (m, 1H), 4.45-4.48 (dd, 1H), 4.59-4.62 (dd, 1H), 4.82 (m, 1H), 5.20-5.24 (m, 2H), 5.45 (s, 2H), 5.67 (brs, 1H), 6.73 (brs, 1H), 8.07 (m, 1H), 8.38-8.44 (m, 1H), 9.14-9.18 (m, 1H), 9.43 (brs, -2NHs), 9.65 (s, 1H). Exemplary spectrum is shown in FIG. 17.

[0200] Example 4. Synthesis of compound 9b This example provides an exemplary method for the synthesis of compound 9b of Synthetic Scheme 1 shown in Example 1. [ka]

[0201] A clean, dry round bottom flask was charged with compound 8b under nitrogen, followed by degassed DI water. This solution was diluted with NaHCO 3Add Na 2 S 2 O 4 was added portionwise and stirred for 1-2 min. Degassed ethyl acetate was then added and the resulting mixture was stirred at room temperature for 4 h, followed by an aqueous workup using DI water and ethyl acetate. The aqueous layer was extracted twice with degassed ethyl acetate and the organic layers were combined, dried and evaporated under reduced pressure to give the desired compound.

[0202] 1 H NMR (400 MHz, CDCl 3 ) ppm: 7.13 (2H, s), 5.24-5.27 (m, 2H), 5.18 (t, 2H, J= 12.6 Hz), 5.94 (dd, 2H, J= 1.3, 8.1 Hz), 5.6 (brs, 2H, NH2), 4.93 (d,2H, J= 6.9 Hz), 4.83-4.86 (m, 2H), 4.27-4.36 (dd, 4H, J= 4.9 Hz, 11.9 Hz), 4.17 (m, 2H), 3.11 (brs, 4H), 2.76-2.87 (brm, 4H), 2.10 (s, 6H, 3-OAc), 2.08 (s, 6H, 3-OAc). 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.3, 20.5, 22.9, 28.7, 63.6, 70.6, 70.8, 78.8, 93.1, 102.8, 104.1, 125.6, 135.3, 152.6, 169.5, 171.9; MS: found m / z = 763.11 (M+l). Calculated for C 34 H 42 N 4 O 16 : 763.2674 (M+1). Exemplary spectra are shown in Figures 18A-C.

[0203] Example 5. Synthesis of compound 10(ah) This example provides an exemplary synthesis method for compound 10(ah) of Synthetic Scheme 1 shown in Example 1. The structure of compound 10(ah) is shown below. [ka]

[0204] In a clean round bottom flask, NR-lauric acid (NRLR) triflate was dissolved in a 1:1 mixture of water and acetonitrile, and the resulting mixture was cooled on ice to 0-5 °C and stirred at the same temperature for 15-20 min. To this ice-cold solution, Amberlite resin was added and stirred at 0-5 °C for 2 h. A glass column was packed with Amberlite resin and the column was equilibrated with DI water. The above mixture of NRLR triflate and Amberlite resin was added to the column and eluted using a 1:1 mixture of water and acetonitrile.

[0205] The collected fractions were combined and evaporated under reduced pressure to give a white powder of NRLR chloride free of triflate ions. 1 H NMR and 19 F NMR analysis confirmed ion exchange from triflate to chloride. 19 The absence of fluorine peaks in F NMR confirmed the complete conversion of the corresponding triflate salt to the chloride. 1 1 H NMR revealed the expected chemical shifts associated with NRLR triflate and the desired peaks for NRLR chloride slightly altered by ion exchange.

[0206] Reaction conditions and ion exchange chromatography were optimized to obtain compounds of the desired purity. Conditions were modified and carefully adjusted to avoid column chromatography that would otherwise lead to deacetylated impurities.

[0207] Synthesis of compound 10g from crude compound 8g Crude compound 8g was obtained as described in the synthesis of compound 8g in Example 3 (Protocol 2). The crude compound obtained was converted to the chloride salt by Amberlite exchange chromatography, and the resulting chloride derivative (compound 10g) was purified by Teledyne reversed-phase C18 column chromatography. The desired fractions were collected, evaporated, dried, and 1 HNMR and 13 Compound 10g was analyzed by CNMR and found to be pure and free of any traces of nicotinamide (NAM) or other impurities.

[0208] It was found that by using certain reaction conditions, purification by column chromatography can be avoided. The protocol for synthesizing compound 10g without column purification is as follows:

[0209] A ball mill jar was charged with laurate intermediate 6g (100 mg, 0.21 mmol, 1 equiv.), and NAM-TMS (compound 7) (41 mg, 0.21 mmol, 1 equiv.), followed by trimethylsilyl trifluoromethanesulfonate (76 μL, 0.42 mmol, 2 equiv.), and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. The progress of the reaction was monitored. 1 The reaction was monitored by HNMR. After the reaction was completed, the reaction mixture was cooled to room temperature and then dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure, and the resulting compound was co-distilled twice with diethyl ether (10-15 mL) and dried under high vacuum to obtain a pale yellow syrup (150 mg, 100% yield). 1 HNMR analysis confirmed that the purity was 90-95% and free of NAM impurities. The compound was subjected to Amberlite-Cl ion exchange chromatography without further purification.

[0210] 1 H NMR (400 MHz, D 2O) ppm: 9.36 (s, 1H), 9.1 (d, 1H, J= 6.3 Hz), 9.0 (d, 1H, J= 8.2 Hz), 8.28 (dd, 1H, J= 9.0, 6.1 Hz), 6.59-6.6 (d, 1H, 1'- ribose Hs, J= 4.3 Hz), 5.45-5.47 (t, 1H, 2'- ribose Hs, J= 5.0 Hz), 5.28-5.31 (t, 1H, 3'- ribose Hs, J= 5.0 Hz), 4.73-4.74 (br m, 1H, 4'- ribose Hs), 4.41 (br d, 2H, 5'-riboseHs), 2.26-2.31 (br m, 2H, -CH 2 CO), 2.09 (s, 3H), 1.99 (s, 3H), 1.42-1.43 (br m, 2H), 1.11 (br m, 16H), 0.71 (t, 3H, J= 5.9 Hz); 13 C NMR (400 MHz, D 2 O) ppm: 13.74, 19.76, 19.85, 22.48, 24.55, 28.88, 29.24, 29.4, 29.54, 29.56, 31.77, 33.57, 62.71, 69.79, 75.84, 82.59, HRMS: Calculated C 27 H 41 N 2 O 8 Cl: 556.2551; C 27 H 41 N 2 O 8 .: 521.2863; found 521.2909 (M+). Ion exchange chromatography of NR-triacetate (NRTA) to NRTA chloride [ka]

[0211] A clean round-bottom flask was charged with 100 mg of NR-triflate (compound 8j), a 1:1 mixture of acetonitrile and water (2:2 mL, respectively) was added, and the mixture was cooled on ice for 15 min. To the ice-cold mixture, Amberlite-Cl resin (1.5 g) was added, and the reaction mixture was stirred at 0–5 °C for 2 h. A glass column was packed with Amberlite-Cl resin and equilibrated with a 1:1 mixture of acetonitrile and water. The ice-cold mixture of compound 8j in Amberlite-Cl resin was added to the column and eluted with a 1:1 mixture of acetonitrile and water. The obtained fractions were collected, distilled, dried, and 1 HNMR and 19 FNMR analysis. 1 NRTA peaks were confirmed in HNMR. 19 FNMR showed the disappearance of the fluorine peak, indicating that the ion exchange was successful. The resulting compound was confirmed to be NRTA chloride (compound 10j) (yield: 89%).

[0212] An exemplary example of NRTA triflate before ion exchange 1 HNMR and 19 The FNMR spectra are shown in Figures 24A and 24B, respectively. Figure 25A shows an exemplary NMR spectrum of NRTA triflate after ion exchange. 1 The H NMR spectrum (top) is compared with the spectra before and during ion exchange (middle and bottom, respectively). 19 The FNMR spectrum (top) is compared with the spectra before and during ion exchange (middle and bottom, respectively).

[0213] Ion exchange chromatography of compound 8g to compound 10g after column chromatography In a clean round-bottom flask, NR-laurate (NRLR) (compound 8g) (150 mg, 0.22 mmol) was dissolved in a 1:1 mixture of water and acetonitrile (3 mL each), and the resulting mixture was cooled to 0-5 °C on ice and stirred for 15-20 min. To this ice-cold solution, Amberlite resin (1.5 g) was added and stirred at 0-5 °C for 2 h. A glass column was packed with Amberlite-Cl (IR-410) resin (5 g) and the column was filled with ACN:H 2 The column was equilibrated with a 1:1 mixture of 0. An ice-cold mixture of NRLR (compound 8 g) and Amberlite resin was added to the column and eluted using a 1:1 mixture of water and acetonitrile (50 mL). [ka]

[0214] The collected fractions were combined and evaporated under reduced pressure to give a white powder of NRLR chloride free of triflate ions. 1 H NMR and 19 F NMR analysis confirmed ion exchange from triflate to chloride. 19 The absence of fluorine peaks in F NMR confirmed the complete conversion of the corresponding triflate salt to the chloride. 1 H NMR revealed the expected peaks for NRLR chloride with slight changes in chemical shifts associated with NRLR triflate upon ion exchange. The compound obtained was confirmed to be NRLR chloride (compound 10g) (yield: 85%).

[0215] FIG. 26A and FIG. 26B show an exemplary chromatogram of compound 10g (NRLR-Cl) after column purification and ion exchange. 1 H NMR and 19 FIG. 27 shows the F NMR spectrum of D before ion exchange chromatography. 2 NRLR in O (bottom) and D after ion exchange chromatography 2 An exemplary embodiment of NRLR-Cl (top) in O 19FIG. 28 shows exemplary F NMR spectra of NRLR-Cl after column and ion exchange (top), NRLR after column purification (middle), and NRLR before column purification (bottom). 1 The H NMR spectrum is shown. Ion exchange chromatography of compound 8g to compound 10g without column chromatography [ka]

[0216] A clean round bottom flask was charged with 140 mg of NRLR-triflate (compound 8g), a 1:1 mixture of acetonitrile and water (3:3 mL, respectively) was added, and the mixture was cooled on ice for 15 min. Amberlite-Cl resin (1.5 g) was added to the ice-cooled mixture, and the reaction mixture was stirred at 0-5 °C for 2 h. A glass column was packed with Amberlite-Cl resin and equilibrated with a 1:1 mixture of acetonitrile and water. An ice-cold mixture of compound 8g in Amberlite-Cl resin was added to the column and eluted with a 1:1 mixture of acetonitrile and water. The obtained fractions were collected, distilled, dried, and subjected to ether washing. After ether washing, a white solid was obtained, which was dried and 1 HNMR and 19 FNMR analysis. 1 NRTA peaks were observed in HNMR. 19 The disappearance of the fluorine peak in FNMR indicated that the ion exchange was successful. The compound obtained was confirmed to be NRLR-chloride (10 g, 60% yield).

[0217] FIG. 29 shows an exemplary NRLR without column chromatography ("Crude NRLR"). 1 1 H NMR spectra are shown. FIG. 30 shows an exemplary crude NRLR before (top panel) and after (bottom panel) ion exchange. 1 31A shows an exemplary H NMR spectrum of crude NRLR after ion exchange. 19Figure 31B shows an exemplary mass spectrum of NRLR. Figure 32 shows an exemplary mass spectrum of crude NRLR after ion exchange (top panel) and before ion exchange (bottom panel). 19 F NMR spectrum is shown. The results in Figures 29-32B show that the chloride salt of NRLR can be easily produced from crude compound 8g without column chromatography by using Amberlite as an anion exchange and purification process.

[0218] Reverse phase column chromatography of compound 10g The crude compound obtained from the Voerbruggen reaction (NRLR-OTf, compound 8g with a purity of about 80% by NMR) was subjected to ion exchange chromatography to obtain compound 10g. Compound 10g (about 80% purity, 500 mg) was purified by Teledyne reverse-phase C18 column chromatography using a mixture of acetonitrile and water to obtain pure compound 10g (NRLR-Cl) as a white solid (250 mg, 50% yield). The desired compound was eluted in 25-30% acetonitrile in water. Figures 33A, 33B, 33C, and 33D show an exemplary image of compound 10g after reverse-phase column chromatography. 1 H NMR, 19 F NMR, 13 C NMR and HSQC spectra are shown, respectively.

[0219] Example 6. Synthesis Scheme 2 In this example, an exemplary synthesis method is shown below as Synthesis Scheme 2: [ka]

[0220] Synthesis of compound 12 A clean, dry ball mill jar was charged with monofunctionalized PEG-2000, followed by succinic anhydride, DMAP, trimethylamine, and 1-2 drops of 1,4-dioxane. The contents were ball milled in a Retsch MM400 mill for 30 min at 30 Hz. After 30 min, the reaction mixture was cooled to room temperature and dissolved in 1,4-dioxane. The resulting solution was precipitated with diethyl ether to give a white precipitate, which was dried and carried on to the next step without further characterization.

[0221] A solution-based reaction (i.e., in a reaction vessel instead of a ball mill) was also performed and the same results were reproduced. Proton NMR was indistinguishable between both reaction formats.

[0222] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.61-2.68 (m, 4H), 3.38 (s, 3H), 3.46 (t, 2H, J= 4.6 Hz), 3.53-3.56 (m, 4H), 3.6-3.73 (br m, ~ 180 H), 3.83 (m, 2H), 4.26 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) ppm: 29.6, 31.9, 39.6, 58.9, 63.6, 68.9, 70.4, 71.0, 106.4, 141.9, 175.0, 191.7.

[0223] Synthesis of compound 6i A clean, dry ball mill jar was charged with compound 12, followed by compound 4, EDCI, DMAP, and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill for 90 min at 30 Hz. After 90 min, the reaction mixture was dissolved in dichloromethane, placed in a flask, and evaporated under reduced pressure to yield a white powder. A downfield shift of the 5'Hs of compound 4 indicates successful coupling.

[0224] A solution-based reaction (i.e., in a reaction vessel instead of a ball mill) was also performed and the same results were reproduced. Proton NMR was indistinguishable between both reaction formats.

[0225] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.08 (s, 3H), 2.11 (s, 3H), 2.13 (s, 3H), 2.66 (m, 4H), 2.87 (m, 2H), 3.38 (s, 3H), 3.46 (m, 2H), 3.6 -3.8 (br m, ~ 180 H), 4.2 (m, 1H), 4.25 (m, 2H), 4.35 (m, 1H), 5.32 (m, 2H), 6.15 (br s, 1H). 13 C NMR (100 MHz, CDCl 3 ) ppm: 20.4, 21.05, 28.8, 59.02, 61.6, 63.8, 63.9, 63.99, 69.0, 70.2, 70.3 (very strong, indicative of PEG carbons), 70.4, 71.9, 72.7, 74.1, 98.1. An exemplary spectrum is shown in FIG. 19.

[0226] Synthesis of compound 8i A ball mill jar was charged with intermediate 13 (53 mg, 0.02 mmol) and compound 7 (4.2 mg, 0.02 mmol), followed by trimethylsilyl trifluoromethanesulfonate (9 μL, 0.03 mmol) and 1-2 drops of anhydrous dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. After 30 min, the reaction mixture was cooled to room temperature and dissolved in a flask using acetone. The resulting solution was distilled under reduced pressure and dried to give compound 8i, an off-white hygroscopic solid. The product was confirmed by NMR.

[0227] 1H NMR (400 MHz, Acetone-d6) ppm: 2.08 (s, 6H), 2.53 (s, 3H), 3.26-3.7 (m, cluster H's, polymer), 3.8-4.9 (m, polymer Hs ~ 180 H, 4'H, 3'H), 5.16-5.19 (m, 2H), 5.97 (s, 1H), 8.01 (m, 1H), 8.3 (m, 1H), 9.14 (m, 1H), 9.34 (m, 1H). An exemplary spectrum is shown in FIG.

[0228] Example 7. Synthesis Scheme 3 In this example, an exemplary synthesis method is shown below as Synthesis Scheme 3. [ka]

[0229] Synthesis of compound 16 To a solution of polyethylene glycol (molecular weight: ∼2000, 1 g, 1 eq, 0.5 mmol) in 1,4-dioxane (15 ml) was added succinic anhydride (60 mg, 1.1 eq, 0.6 mmol), DMAP (61 mg, 1 eq, 0.5 mmol) and triethylamine (50 mg, 1 eq, 0.5 mmol). The resulting solution was stirred under argon at room temperature for 24 hours. The desired product was then precipitated using diethyl ether, filtered and dried to give a white solid.

[0230] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.62-2.66 (m, 8H), 3.45-3.48 (m, 5H), 3.64-3.73 (m, ~ 180 H), 3.81 (t, 2H, J = 4.5 Hz), 4.26 (t, 2H, J = 4.6 Hz).

[0231] Synthesis of compound 17 A clean, dry ball mill jar was charged with a mixture of PEG-COOH (50 mg, 0.02 mmol), intermediate 4 (13 mg, 0.04 mmol), DCC (10 mg, 0.04 mmol), DMAP (catalytic amount), and 1-2 drops of dichloromethane. The resulting mixture was ball milled in a Retsch MM400 mill at 30 Hz for 30 min. The resulting mixture was collected in a flask with DCM and evaporated under reduced pressure to obtain the crude compound.

[0232] 1 H NMR (400 MHz, CDCl 3 ) ppm: 2.07-2.17(s, 18H), 2.67 (m, 8H), 3.5-3.79 (br m, ~ 180 H), 4.04 (m, 4H), 4.23-4.44 (m, 6H), 5.33 (m, 4H), 6.16 (br s, 2H). An exemplary spectrum is shown in FIG.

[0233] Synthesis of compound 18 Compound 18 is obtained from compound 17 by carrying out a reaction similar to that described above for synthesizing compound 8i from compound 6i.

[0234] Example 8. Examination of NAD loading ability Exemplary considerations are provided for testing whether the compounds described herein can contribute to the cellular NAD pool.

[0235] Part 1: Evaluation of compounds as precursors for NAD biosynthesis. HepG3 cells are cultured in vitamin B3-deficient RPMI+dialyzed FBS medium for 72 hours. Compounds of formula 5, formula 7, and / or formula 9 are added to the culture at a concentration equivalent to 6 μM vitamin B3. Cell survival is measured after 24 and 48 hours using the CellTiter-Fluor® viability assay.

[0236] Part 2: Evaluation of compounds as direct precursors of the NAD(H) pool. Cells from part 1 of this study that can actively rescue vitamin B3 deficiency are evaluated under the same conditions and in the presence of FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Upon inhibition of NAMPT, cells will only survive if supplemented compounds of formula 5, formula 7, and / or formula 9 can directly rescue the cellular NAD content.

[0237] Example 9. Stability of NRLR-Cl and NRLR-OTf esters The aqueous solubility of the triflate and chloride forms of NRLR esters is very different; i.e., the chloride form of NRLR dissolves in water, while the triflate form does not. To ensure that stability, rather than solubility, could be investigated, both the triflate and chloride forms of NRLR ("NRLR-OTf" and "NRLR-Cl", respectively) were tested for stability in aqueous buffers and as substrates for the enzyme purine nucleoside phosphorylase (PNP). The release of nicotinamide (NAM) was measured, indicative of water-catalyzed hydrolysis. In addition, the release of ribose versus phosphoriboside was observed, indicative of PNP activity. Loss of esters by hydrolysis under buffer-catalyzed conditions also occurs over time. Once the C5-hydroxyl is free, PNP recognizes the nucleoside and catalyzes phosphorolysis. It is unclear whether this hydrolysis must occur for all esters before PNP can act on the nucleoside. The following schematic illustrates the reaction with a partially deprotected nucleoside.

[0238] NR triacetate (NRTA) is more stable to PNP than NR, therefore, esters of NRTA and NRLR-Cl may be suitable precursors of NR in circulation. [ka]

[0239] PNP enzyme activity assay Phosphorolysis of NRCl by PNP (Sigma Aldrich) was performed using KH 2 PO 4 and 10%D 2 Perform at 25 °C in HEPES buffer containing HO. 1 Monitored by 1 H NMR.

[0240] Incubations were carried out in NMR tubes containing 100 mM KH 2 PO 4 450 μl of HEPES buffer (100.0 mM, pH 7.0) containing 50.0 μl of NRCl (1 mL of D 2 The mixture contained 100.0 mM in 200 and 5 μl of PNP (1 mg dissolved in 50 μl of HEPES buffer) was added at the appropriate time to contain a final volume of 505 μl, and measurements were taken at t = 5 and 15 min.

[0241] The results are shown in Figures 34A, 34B, and 34C. Complete conversion of NR to NAM occurred within 5 min, indicating the ability of the enzyme to perform glycosidic bond cleavage (Figures 34A and 34B, top panels). NRTA was found to be stable to PNP. This is due to the 5'-acetyl group conferring resistance to PNP activity (Figure 34B, panels 2 to 4, and Figure 34C). After 24 h, NRTA is very slowly hydrolyzed, releasing NAM. Slow partial ester hydrolysis is also observed as a new series of "NR" peaks emerge. This result indicates that over time, the NR triester slowly releases NR by simple chemical hydrolysis (saponification).

[0242] Note: Compound 8g (NRLR triflate) was not completely soluble in water and was therefore dissolved in DMSO for PNP activity. Similarly, PNP studies of NRAD triflate were performed in DMSO. 1 The H NMR spectrum is shown in Figure 35.

[0243] Lipase assay NRLR was subjected to lipase assay in 10% DMSO, 450 μL HEPES buffer, and enhanced lipase (Candida rugens). The results are shown in Figure 36 and show that after 12 hours of incubation with lipase, NRLR remained almost completely intact with only partial loss of one ester (<5%). Figure 37 further shows that incubation with increasing concentrations of lipase for 12 hours had no effect on NRLR, confirming that NRLR is stable to lipase in HEPES buffer.

[0244] Stabilization of laurate by PNP The effect of PNP on compound 8g (NRLR) was studied at various time intervals, with an overall increase in NAM of 17% at 24 h. In addition, partial deprotection of the esters is observed over time, as shown for example by the sharper peak at 9.5 ppm in Figure 38. This indicates that the C5-ester is partially released over time, likely due to the lipid chain of the laurate salt being responsible for rotational restriction and broadening of the peak in the NMR spectrum.

[0245] Dimer stabilization by PNP The effect of PNP on compound 8d (NR adipate) was examined at various time intervals, with an overall increase in NAM of 6.3% at 18 hours. NR adipate appears to be stable to PNP, as shown in Figure 39. Hydrolysis of the nucleoside bond prevailed, while the ester dimer appeared to remain intact.

[0246] PNP activity assay against NRCl, compound 8d, compound 8a, and compound 8g The effect of PNP on NRCl, compound 8d (NR adipate or NRAD), compound 8a (NR malonate or NRML), and compound 8g (NRLR) was compared over a two day period. Results after one day are shown in Figure 40A. NRCl was completely degraded to NAM within 15 min of PNP addition, while NR adipate, NR malonate, and NRLR showed a 3-4%, 23%, or 30% increase in NAM, respectively, after one day.

[0247] The results after 2 days are shown in Figure 40B. After 2 days, NRLR (compound 8g) was almost completely (~90%) degraded to NAM, while NR adipate (compound 8d) and NR malonate still showed some NR diester peaks.

[0248] conclusion As shown in this example, NRCl is the least stable to the PNP enzyme and is degraded within a few minutes (5-10 minutes) after the addition of PNP. PNP degrades NR to NAM and ribose 5'-phosphate. DMSO or HEPES do not affect the enzyme activity, either in combination or mixed. The enzyme activity was significantly improved with DMSO or D 2 There is no difference in O. Lipase does not cause deacetylation even at high concentrations or for long periods of time. NRTA is more stable to PNP than NRCl. NR laurate (monoester) is less stable than NR adipate (diester). NR malonate is less stable than NR adipate. Partial deacetylation was observed with NR diester in addition to NAM and ribose phosphate.

[0249] The overall trend in the stability of NR esters against PNP is as follows:

[0250] NRTA > NRAD > NRML > NRLR > NRCl

[0251] Example 10. Determination of lipophilicity of NRLR-Cl The octanol-water partition coefficient (Pow) of NRLR-Cl (compound 10g) was determined. As discussed in Lipinski et al., Adv Drug Deliv Rev 23(l-3):3-25 (1997), the logPow of a compound intended for oral administration should be less than 5. The predicted logPow of NRLR-Cl as determined by BIOVIA DRAW 2019™ software is 2.0284.

[0252] The experiments were carried out as described in “Measuring Lipophilicity with NMR,” SpinSolve CarbonR, MagriTek (2014). 2 Regarding NRLR-Cl in O 1 A H NMR spectrum was recorded, and then an equivalent amount of 1-octanol was added to the same NMR tube. 1 H NMR was recorded again. Measurements were performed in triplicate. D was determined based on the NMR peak values. 2 The POW was calculated based on the NRLR-Cl concentrations in the O and octanol layers, and the results are shown in Table 1. The average measured logPOW of NRLR-Cl is 1.816. [Table 1]

Claims

1. A compound represented by any one of the following formulas 1 to 9: A-R1-A' (Formula 1) In the formula 1, A and A' are independently a hydrogen atom or 【Chemistry 1】 and where A and A' are not both hydrogen atoms, and: When one of A or A' is a hydrogen atom, R1 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, or alkenylaryl; or When A and A' are not both hydrogen atoms, R1 is a substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl, alkyl polyethylene glycol (PEG) ester, or C1-C3 alkyl carboxylate optionally substituted with a protected or free amine; and Ac is an acetyl group; 【Chemistry 2】 wherein R2 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; and Ac is an acetyl group; 【Transformation 3】 wherein R3 is a substituted or unsubstituted alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 4 carbon atoms, or alkylcarboxylate having 1 to 3 carbon atoms optionally substituted with a protected or free amine; Alternatively, R3 is (i) a hydroxy group and (ii) one of the following: 【Chemistry 4】 and Ac is an acetyl group; BR1-B' (Formula 4) wherein B and B' are independently a hydrogen atom or 【Transformation 5】 and where B and B' are not both hydrogen atoms, and When either B or B' is a hydrogen atom, R1 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, or alkenylaryl; or When B and B' are not both hydrogen atoms, R1 is a substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, PEG ester alkyl, or C1-C3 alkyl carboxylate optionally substituted with a protected or free amine; R4 is a nucleobase; and Ac is an acetyl group; C-R1-C' (Formula 5) wherein C and C' are independently a hydrogen atom or 【Transformation 6】 and where C and C' are not both hydrogen atoms, and: When one of C or C' is a hydrogen atom, R1 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, or alkenylaryl; or When C and C' are not both hydrogen atoms, R1 is a substituted or unsubstituted C1-C4 alkyl, C1-C4 alkenyl, PEG ester alkyl, or C1-C3 alkyl carboxylate optionally substituted with a protected or free amine; R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group; 【Transformation 7】 wherein R2 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; R4 is a nucleobase; and Ac is an acetyl group; 【Transformation 8】 wherein R2 is a substituted or unsubstituted alkyl having 8 to 24 carbon atoms, alkenyl having 8 to 24 carbon atoms, aryl, alkylaryl, alkenylaryl, or PEG ester alkyl; R5 is nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group; 【Chemistry 9】 wherein R3 is a substituted or unsubstituted alkyl having 1 to 4 carbon atoms, alkenyl having 1 to 4 carbon atoms, or alkyl having 1 to 3 carbon atoms optionally substituted with a protected or free amine; or R3 is (i) a hydroxy group and (ii) 【Chemistry 10】 containing a carbon bonded to either of R4, R4', and R4" are each independently a nucleobase; and Ac is an acetyl group; 【Chemistry 11】 wherein R3 is a substituted or unsubstituted alkyl having 1 to 4 carbon atoms, alkenyl having 1 to 4 carbon atoms, or alkyl having 1 to 3 carbon atoms optionally substituted with a protected or free amine; or wherein R3 is (i) a hydroxy group and (ii) 【Chemistry 12】 a carbon bonded to either of wherein R5, R5', and R5'' are each independently nicotinamide, dihydronicotinamide, nicotinic acid, nicotinic acid ester, or reduced forms thereof; and Ac is an acetyl group.

2. 2. The compound of claim 1, wherein the compound is a compound of Formula 1, Formula 4, or Formula 5, and R1 is an alkyl PEG ester.

3. 3. The compound of claim 2, wherein the PEG ester alkyl comprises 10 to 100 ethylene glycol units.

4. The compound is a compound of Formula 2, Formula 6 or Formula 7, wherein R2 is: alkyl having 12 carbon atoms, alkenyl having 18 carbon atoms, alkenyl having 20 carbon atoms, or alkenyl having 22 carbon atoms; substituted or unsubstituted phenyl or benzyl, optionally benzyl containing an amino substituent or para-aminobenzyl; mycophenolate; or alkyl PEG esters optionally containing 10 to 100 ethylene glycol units; 2. The compound of claim 1, wherein:

5. the compound is a compound of formula 2, formula 6 or formula 7, 【Chemistry 13】 is a substituted or unsubstituted palmitoyl group, oleoyl group, linoleoyl group, linolenoyl group, arachidonoyl group, eicosapentaenoyl group, or docosahexaenoyl group; Retinol succinate; or Omega-3 fatty acid esters; 2. The compound of claim 1, wherein:

6. The compound is a compound of formula 3, and the compound of formula 3 is 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 Either The compound according to claim 1, which is a mixture thereof.

7. The compound is a compound of Formula 3, Formula 8, or Formula 9, wherein R3 is: unsubstituted alkyl having 1 to 4 carbon atoms; alkenyl having 2 carbon atoms; Boc-protected amine-substituted alkyl having 1 to 3 carbon atoms; an N-Boc-protected glutamate or aspartate-substituted C1-C3 alkyl; or 【Chemistry 20】 is an alkyl having 3 carbon atoms substituted with The compound of claim 1.

8. The compound is a compound of formula 8, and the compound of formula 8 is 【Chemistry 21】 2. The compound of claim 1, wherein:

9. The compound is a compound of formula 9, wherein the compound of formula 9 is 【Chemistry 22】 2. The compound of claim 1, wherein:

10. A method for making a compound of Formula 1, Formula 2, or Formula 3, comprising: (a) adding a protecting group to the 5'-carbon of D-ribose to form a 5'-protected ribose; (b) acetylating the hydroxy groups at the 1', 2', and 3' carbons of the 5'-protected ribose to form an acetylated 5'-protected ribose; (c) deprotecting the 5'-carbon of the acetylated 5'-protected ribose to form an acetylated 5'-deprotected ribose; and (d) coupling the acetylated 5'-deprotected ribose with a reactant comprising R1, R2, and / or R3 to form the compound of Formula 1, Formula 2, or Formula 3.

11. The method of claim 10, wherein the coupling is carried out by a mechanochemical reaction.

12. 12. The method of claim 10 or 11, wherein the reactants of (d) comprise an acid chloride, an acid anhydride, a dicarboxylic acid, or a monocarboxylic acid of R1, R2, and / or R3.

13. A method for preparing a compound of any of formulas 4 to 9, comprising: reacting a compound of Formula 1, Formula 2, or Formula 3 with a functionalized nucleobase to form said compound of Formula 4, Formula 5, or Formula 6; or reacting a compound of Formula 1, Formula 2, or Formula 3 with a functionalized nicotinamide to form said compound of Formula 7, Formula 8, or Formula 9; A method comprising:

14. The method of claim 13 , wherein the reaction is carried out by a mechanochemical reaction.

15. 10. A composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

16. 10. A compound according to any one of claims 1 to 9 for use in treating nicotinamide adenine dinucleotide (NAD) deficiency in a subject in need of NAD.

17. 10. A compound according to any one of claims 1 to 9 for use in increasing nicotinamide adenine dinucleotide (NAD) in a subject in need thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and pterostilbene.

19. 19. The pharmaceutical composition of claim 18 for the treatment of nicotinamide adenine dinucleotide (NAD) deficiency.

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